WO2010026365A1 - N-myristoyl transferase inhibitors - Google Patents

N-myristoyl transferase inhibitors Download PDF

Info

Publication number
WO2010026365A1
WO2010026365A1 PCT/GB2009/002084 GB2009002084W WO2010026365A1 WO 2010026365 A1 WO2010026365 A1 WO 2010026365A1 GB 2009002084 W GB2009002084 W GB 2009002084W WO 2010026365 A1 WO2010026365 A1 WO 2010026365A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
ring
optionally substituted
alkyl
formula
Prior art date
Application number
PCT/GB2009/002084
Other languages
French (fr)
Inventor
Stephen Brand
Paul Wyatt
Original Assignee
University Of Dundee
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University Of Dundee filed Critical University Of Dundee
Priority to US13/061,811 priority Critical patent/US9156811B2/en
Priority to EP09785018.4A priority patent/EP2323987B1/en
Priority to ES09785018.4T priority patent/ES2546865T3/en
Publication of WO2010026365A1 publication Critical patent/WO2010026365A1/en
Priority to US14/840,660 priority patent/US9828346B2/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C07D231/42—Benzene-sulfonamido pyrazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/69—Benzenesulfonamido-pyrimidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • C07D263/50—Benzene-sulfonamido oxazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds and their use as N-myristoyl transferase inhibitors.
  • the modification of proteins by myristoylation is required for the subcellular targeting, protein conformation and biological activity of many important proteins in eukaryotic cells, including those required for signal transduction and regulatory functions important in cell growth (Towler et al. J Biol Chem 1987; 262:1030 - 6. 20: Wolven et al. MoI Biol Cell 1997; 8:1159 - 73.).
  • the myristoylation reaction the transfer of myristic acid from myristoyl-coenzyme A (CoA) to the amino groups of terminal glycine residues, is catalysed by the ubiquitously distributed enzyme N-myristoyl-CoA: protein, N-myristoyl transferase (NMT).
  • the reaction requires only myristoyl-CoA and a protein containing a suitable peptide sequence, and occurs through an ordered Bi Bi mechanism.
  • This modification occurs primarily as a cotranslational process (Wilcox et al. Science 1987, 238:1275 - 8. 22; Deichaite et al. MoI Cell Biol 1988; 8:4295 - 301), although myristoylation can also occur post-translationally (Pillai et al. Proc Natl Acad Sci USA 1987; 84:7654 - 8. 24: King et al. J Biol Chem 1989; 264:7772- 5.).
  • NMT N-myristoyltransferase
  • Plasmodium falciparum NMT Screening of recombinant Plasmodium falciparum NMT has identified a series of benzothiazole analogues with IC 5O values ⁇ 50 ⁇ M, with selectivity over human NMT1. Two of compounds of the series when tested at a concentration of 10 ⁇ M against cultured parasites in vitro reduced parasitemia by >80%. (Bowyer et al., Biochemical Journal (2007), 408(2), 173-180.)
  • NMT1 and NMT2 Two isozymes of the mammalian NMT enzymes, NMT1 and NMT2, have been cloned and share -77% identity (Giang DK, Cravatt BF. A second mammalian N- myristoyltransferase. J Biol Chem 1998; 273:6595 - 8.) with the majority of divergence occurring in the amino-terminal domains. Splice variants of NMT1 have also been observed in some cells. Possibly these amino-terminal variations allow differential cellular localization of the isozymes, thereby allowing either cotranslational ribosome-based or post-translational cytosol-based protein myristoylation.
  • NMT1 and NMT2 have similar, but distinguishable, relative selectivity, as shown by an in vitro comparison of the activity of the isozymes on a limited panel of substrate peptides. (Giang and Cravatt, J Biol Chem 1998; 273:6595 - 8. 27; Aitken A, Biochem Soc Trans 1989; 17:871 - 5.).
  • myristoylation is still being elucidated; however evidence of its involvement in many disease states, such as cancer (Selvakumar, P. et al., Progress in Lipid Res., 2006, (46), 1-36), epilepsy (Selvakhumar, P. et al., Biochem. Biophys Res. Comm. 2005, (335), 1132-1139), Alzheimer's disease, ischemia, diabetes, HIV (Shoji, S. et al., JP2006223173) and osteoporosis is growing.
  • Cellular myristoylated proteins have diverse biological functions in oncogenesis and signal transduction.
  • Examples include the catalytic subunit of cAMP4-dependent protein kinase, various tyrosine kinases (pp ⁇ Osrc, pp60yes, pp ⁇ lck, pp59fyn/syn, and c-Abl), the ⁇ -subunit of calcineurin (Lakshmikuttyamma, A et al., Progress in Neurobiol. 2008, 84 (1), 77-84) the myristoylated alanine-rich C kinase substrate, and the ⁇ -subunit of several guanine nucleotide binding proteins and ADP ribosylation factors.
  • NMT activity and expression has been shown in a number of tumour types, suggesting inhibitors of NMT would be potential anti-cancer agents.
  • Src family of tyrosine kinases e.g., c-Src, Yes, and Fyn
  • c-Src, Yes, and Fyn Src family of tyrosine kinases
  • Fyn Fyn-dependent tyrosine kinases
  • Functionally characterization of the two NMT isozymes in human cells using unique small interfering RNAs (siRNA) for each isozyme were shown to decrease NMT1 or NMT2 protein levels by at least 90%. Knockdown of NMT1 inhibited cell replication associated with a loss of activation of c-Src and its target FAK.
  • NMT1 and NMT2 have only partially overlapping functions and that NMT1 is critical for tumour cell proliferation.
  • Viruses and bacteria usually lack N-myristoyltransferases so consequently their proteins are processed by NMTs of their eukaryotic hosts. (Maurer-Stroh et al.,
  • human N- myristoyltransferase catalyzes N-myristoylation of several HIV-1 proteins, including Pr160gag-pol, Pr55gag, the capsid protein p17 derived from proteolytic processing of gag, and neg. factor (nef). N-myristoylation of Pr160gag-pol and Pr55gag is required for viral replication. Reduction in the mRNA levels of human
  • NMT isoforms and NMT activities have been shown in the course of HIV-1 infection in the human T-cell line, CEM.
  • novel synthetic NMT inhibitors were significantly more cytotoxic to chronically HIV-1 infected T-cell line, CEM/LAV-1, compared to uninfected CEM cells.
  • Myristic acid analogues designed as alternative substrates for NMT have shown to inhibit the proliferation of HIV-1 (Bryant et al., Perspectives in Drug Discovery and Design (1993), 1(1), 193-209.; Devadas et al., Bioorganic & Medicinal Chemistry Letters (1993), 3(4), 779-84.) and Hepatitis B (Parang et al., Antiviral Research (1997), 34(3), 75-90.)
  • myristic acid analogues have been shown to inhibit HIV-1 (Adams et al.,Eur. Pat. Appl. (1992), 20 pp.
  • NMT has been shown genetically to be essential for a number of fungal strains, such as Candida albicans (Weinberg et al., Molecular Microbiology (1995), 16(2), 241-50.), Saccharomyces cerevisiae, Cryptococcus neoformans (Lodge et al., PNAS USA (1994), 91(25), 12008-12.) and Aspergillus fumigatus (Cook, WJ et al., US Patent 20020025524 (2002), both in culture and animal models of infection.
  • Candida albicans Weinberg et al., Molecular Microbiology (1995), 16(2), 241-50.
  • Saccharomyces cerevisiae Saccharomyces cerevisiae
  • Cryptococcus neoformans Lodge et al., PNAS USA (1994), 91(25), 12008-12.
  • Aspergillus fumigatus Cook, WJ et al., US Patent
  • the present inventors have provided sulphonamide compounds which are inhibitors of N-myristoyl transferases.
  • the present invention relates to a class of N-heterocyclic sulphonamides and to their use in therapy. More particularly, the invention provides a family of N- heteroarylsulphonamides which are substituted [in the meta- or para- position] by an optionally substituted amine-bearing moiety.
  • a sulphonamide derivative comprising a sulphonamide group linking a N-heterocyclic head group and tail group via an aryl or heteroaryl linker attached to the tail wherein the tail includes a protonatable moiety such as a primary, secondary or tertiary alkylamine (or a protonatable heterocycle such as imidazole).
  • n 0,1, 2, 3, 4, 5 or 6;
  • ring A herein referred to as a "head” group, is an optionally substituted nitrogen containing aryl group wherein each substitutable carbon or nitrogen in Ring A is optionally and independently substituted by one or more R 5 and wherein if Ring A contains an -NH- moiety that nitrogen may be optionally substituted by C- ⁇ -6 alkyl (e.g. methyl); and wherein R 4 and ring A together with the atoms to which they are attached may form a cyclic group.
  • ring B is an optionally substituted aryl or heteroaryl group wherein each substitutable carbon or heteroatom in Ring B is optionally and independently substituted by one or more R 3 ;
  • W and X are independently selected from R 11 , hydrocarbyl (e.g.C 1-8 alkyl, alkenyl, alkynyl.or haloalkyl) optionally substituted with R 11 , and -(CH 2 ) k -heterocyclyl optionally substituted with R 12 ; k is 0, 1 , 2, 3, 4, 5 or 6;
  • R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from hydrogen, R 12 , hydrocarbyl (e.g.Ci- 6 alkyl, alkenyl, alkynyl.or haloalkyl) optionally substituted with R 12 , and - (CH 2 ) ⁇ -heterocyclyl optionally substituted with R 12 ; wherein R 1 and R 2 taken together with the atoms to which they are attached may form a heterocycle, optionally substituted with one or more R 12 ; wherein R 1 and/or R 2 taken together with W or X may form a heterocycle optionally substituted with one or more R 12 ; and wherein one or more of R 3 and R 5 taken together with the atoms to which they are attached may form a carbocycle, for example heterocyclyl, optionally substituted with R 12 ; I is 0, 1 , 2, 3, 4, 5 or 6;
  • R 13 and R 14 are each independently selected from hydrogen or
  • R 15 is selected from hydrocarbyl (e.g.C- ⁇ - 6 alkyl, alkenyl, alkynyl.or haloalkyl), carbocyclyl and -(CH 2 ) m -heterocyclyl, and each R 15 is optionally and independently substituted with one or more of halogen, cyano, amino, hydroxy, C- ⁇ - 6 alkyl or cycloalkyl and C- ⁇ - 6 alkoxy; m is O, 1, 2, 3, 4, 5 or 6;
  • p is O, 1 , 2, 3 or 4; wherein the values of R 4 may be the same or different; q is 0, 1 , 2, 3 or 4; wherein the values of R 5 may be the same or different;
  • a sulphonamide derivative comprising a sulphonamide group linking a heteroaryl head group and an aryl or heteroaryl central group for use as a medicament.
  • n, ring A, ring B, R 3 , R 4 , R 5 , p and q are as defined herein;
  • R 17 and R 18 are each independently selected from hydrogen or R 19 ;
  • R 19 is selected from hydrocarbyl (e.g.Ci- 6 alkyl, alkenyl, alkynyl.or haloalkyl), carbocyclyl and -(CH 2 ) s -heterocyclyl, and each R 19 is optionally and independently substituted with one or more of halogen, cyano, amino, hydroxy, Ci -6 alkyl and Ci -6 alkoxy; s is O, 1, 2, 3, 4, 5 or 6; 8 or a pharmaceutically acceptable salt or pro-drug thereof.
  • hydrocarbyl e.g.Ci- 6 alkyl, alkenyl, alkynyl.or haloalkyl
  • carbocyclyl and -(CH 2 ) s -heterocyclyl each R 19 is optionally and independently substituted with one or more of halogen, cyano, amino, hydroxy, Ci -6 alkyl and Ci -6 alkoxy; s is O, 1, 2, 3, 4, 5 or 6; 8
  • Y is absent and Z is halogen e.g. Br or Cl.
  • ring B is aryl e.g. a 6-membered aromatic ring including benzene.
  • n may be 0 or 1. Preferably n is 0.
  • the compounds of the invention can exist in different forms, such as free acids, free bases, esters and other prodrugs, salts and tautomers, for example, and the invention includes all variant forms of the compounds.
  • hydrocarbyl as used herein includes reference to moieties consisting exclusively of hydrogen and carbon atoms; such a moiety may comprise an aliphatic and/or an aromatic moiety. The moiety may comprise 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms.
  • hydrocarbyl groups include Ci -6 alkyl (e.g. Ci, C 2 , C3 or C 4 alkyl, for example methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl); Ci -6 alkyl substituted by aryl (e.g.
  • benzyl or by cycloalkyl (e.g cyclopropylmethyl); cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl); alkenyl (e.g. 2- butenyl); alkynyl (e.g. 2-butynyl); aryl (e.g. phenyl, benzyl, naphthyl or fluorenyl) and the like.
  • cycloalkyl e.g cyclopropylmethyl
  • cycloalkyl e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl
  • alkenyl e.g. 2- butenyl
  • alkynyl e.g. 2-butynyl
  • aryl e.g. phenyl, benzyl, naphthyl or fluoreny
  • alkyl and “Ci -6 alkyl” as used herein can be used interchangeably and include reference to a straight or branched chain alkyl moiety having 1 , 2, 3, 4, 5 or 6 carbon atoms. This term includes reference to groups such as methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, iso-butyl, sec-butyl or tert- butyl), pentyl, hexyl and the like.
  • alkyl may have 1 , 2, 3 or 4 carbon atoms.
  • Haloalkyl relates to an alkyl radical preferably having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms, substituted with one or more halide atoms for example CH 2 CH 2 Br, CF 3 or CCI 3 .
  • alkenyl and C 2-6 alkenyl as used herein can be used interchangeably and include reference to a straight or branched chain alkyl moiety having 2, 3, 4, 5 or 6 carbon atoms and having, in addition, at least one double bond, of either E or Z stereochemistry where applicable. This term. includes reference to groups such as ethenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3- butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl and 3-hexenyl and the like.
  • alkynyl and “C 2 - 6 alkynyl” as used herein can be used interchangeably and include reference to a straight or branched chain alkyl moiety having 2, 3, 4, 5 or 6 carbon atoms and having, in addition, at least one triple bond. This term includes reference to groups such as ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 2-butynyi, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1- hexynyl, 2-hexynyl and 3-hexynyl and the like.
  • alkoxy and “Ci -6 alkoxy” as used herein can be used interchangeably and include reference to -O-alkyl, wherein alkyl is straight or branched chain and comprises 1, 2, 3, 4, 5 or 6 carbon atoms. In one class of embodiments, alkoxy has 1 , 2, 3 or 4 carbon atoms. This term includes reference to groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, hexoxy and the like.
  • cycloalkyl as used herein includes reference to an alicyclic moiety having 3, 4, 5, 6, 7 or 8 carbon atoms.
  • the group may be a bridged or polycyclic ring system. More often cycloalkyl groups are monocyclic. This term includes reference to groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[2.2.2]octyl and the like.
  • aryl as used herein includes reference to an aromatic ring system comprising 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring carbon atoms.
  • Aryl is often phenyl but may be a polycyclic ring system, having two or more rings, at least one of which is aromatic. This term includes reference to groups such as phenyl, naphthyl, fluorenyl, azulenyl, indenyl, anthryl and the like.
  • carbocyclyl as used herein includes reference to a saturated (e.g. cycloalkyl) or unsaturated (e.g. aryl) ring moiety having 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15 or 16 carbon ring atoms.
  • carbocyclyl includes a 3- to 10-membered ring or ring system and, in particular, a 5- or 6-membered ring, which may be saturated or unsaturated.
  • a carbocyclic moiety is, for example, selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbomyl, bicyclo[2.2.2]octyl, phenyl, benzyl, naphthyl, fluorenyl, azulenyl, indenyl, anthryl and the like.
  • heterocyclyl as used herein includes reference to a saturated (e.g. heterocycloalkyl) or unsaturated (e.g. heteroaryl) heterocyclic ring moiety having from 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15 or 16 ring atoms, at least one of which is selected from nitrogen, oxygen, phosphorus, silicon and sulphur.
  • heterocyclyl includes a 3- to 10-membered ring or ring system and more particularly a 5- or 6-or 7-membered ring, which may be saturated or unsaturated.
  • a heterocyclic moiety is, for example, selected from oxiranyl, azirinyl, 1 ,2- oxathiolanyl, imidazolyl, thienyl, furyl, tetrahydrofuryl, pyranyl, thiopyranyl, thianthrenyl, isobenzofuranyl, benzofuranyl, chromenyl, 2H-pyrrolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, py- ridyl, pyrazinyl, pyrimidinyl, piperidyl, piperazinyl, pyridazinyl, morpholinyl,
  • heterocycloalkyl as used herein includes reference to a saturated heterocyclic moiety having 3, 4, 5, 6 or 7 ring carbon atoms and 1 , 2, 3, 4 or 5 ring heteroatoms selected from nitrogen, oxygen, phosphorus and sulphur.
  • the group may be a polycyclic ring system but more often is monocyclic.
  • This term includes reference to groups such as azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxiranyl, pyrazolidinyl, imidazolyl, indolizidinyl, piperazinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, quinolinidinyl and the like.
  • heteroaryl as used herein includes reference to an aromatic heterocyclic ring system having 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15 or 16 ring atoms, at least one of which is selected from nitrogen, oxygen and sulphur.
  • the group may be a polycyclic ring system, having two or more rings, at least one of which is aromatic, but is more often monocyclic.
  • This term includes reference to groups such as pyrimidinyl, furanyl, benzo[b]thiophenyl, thiophenyl, pyrrolyl, imidazolyl, pyrrolidinyl, pyridinyl, benzo[b]furanyl, pyrazinyl, purinyl, indolyl, benzimidazolyl, quinolinyl, phenothiazinyl, triazinyl, phthalazinyl, 2H-chromenyl, oxazolyl, isoxazolyl, thiazolyl, isoindolyl, indazolyl, purinyl, isoquinolinyl, quinazolinyl, pteridinyl and the like.
  • halogen as used herein includes reference to F, Cl, Br or I. In particular, halogen may be F or Cl.
  • substituted as used herein in reference to a moiety means that one or more, especially up to 5, more especially 1 , 2 or 3, of the hydrogen atoms in said moiety are replaced independently of each other by the corresponding number of the described substituents.
  • optionally substituted as used herein means substituted or unsubstituted.
  • substituents are only at positions where they are chemically possible, the person skilled in the art being able to decide (either experimentally or theoretically) without inappropriate effort whether a particular substitution is possible.
  • amino or hydroxy groups with free hydrogen may be unstable if bound to carbon atoms with unsaturated (e.g. olefinic) bonds.
  • substituents described herein may themselves be substituted by any substituent, subject to the aforementioned restriction to appropriate substitutions as recognised by the skilled man.
  • Ring A is preferably an optionally substituted 5 or 6 membered nitrogen containing heteroaryl.
  • ring A may be an optionally substituted 5 membered nitrogen-containing heteroaryl including, but not limited to, optionally substituted pyrazole, imidazole, imidazoline, triazole or tetrazole.
  • ring A may be an optionally substituted 6 membered nitrogen-containing heteroaryl including, but not limited to, optionally substituted pyridine, 3 amino pyridine, 4 amino pyridine, pyridazine, pyrimidine, pyrazine, triazine and tetrazine.
  • Ring A may be comprise other ring heteroatoms in addition to N for example O or S.
  • ring A may be optionally substituted isoxazole.
  • ring A is selected from optionally substituted pyrazole, pyridine or isoxazole.
  • ring A is optionally substituted pyrazole.
  • n, ring B, W, X, R , R , R ⁇ , R , Rr, p and q are as defined herein.
  • R 5a , R 5b and R 5c are independently selected from hydrogen, R 12 , hydrocarbyl (e.g.C-i- ⁇ alkyl, alkenyl, alkynyl,or haloalkyl) optionally substituted with R 12 , and -(CH 2 ) ⁇ - heterocyclyl optionally substituted with R 12 .
  • ring B is an optionally substituted 5 or 6 membered aryl (e.g. benzene) or heteroaryl wherein each substitutable carbon or heteroatom in ring B may be optionally and independently substituted by halogen for example selected from one or more of F, Cl and Br.
  • Ring B may be a 5 membered aryl containing one or more heteroatoms selected from N, S and O.
  • ring B may be thiophene.
  • ring B may be a 6 membered aryl containing one or more heteratoms selected from N, S and O.
  • ring B may be a 6 membered nitrogen containing heteroaryl, for example pyridine.
  • the invention provides a compound of formula (IV) wherein E is N.
  • the invention provides a compound of formula (IV) wherein E is C.
  • n, W, X, R 1 , R 2 , R 3 , R 4 , R 5 , p and q are as defined herein; and E is independently selected from C and N.
  • n, W, X, R 1 , R 2 , R 4 , R 5 , p and q are as defined herein; and wherein R 3a , R 3b , R 3c and R 3d are independently selected from hydrogen, R 12 , hydrocarbyl (e.g. Ci -6 alkyl, alkenyl, alkynyl,or haloalkyl) optionally substituted with R 12 , and - (CH 2 ) ⁇ -heterocyclyl optionally substituted with R 12 .
  • hydrocarbyl e.g. Ci -6 alkyl, alkenyl, alkynyl,or haloalkyl
  • R 3a , R 3b , R 3c and R 3d are independently selected from hydrogen, halogen (e.g. Cl or F) and Ci -6 alkyl or haloalkyl.
  • R 3a and/or R 3b is halogen for example Cl or F.
  • W is absent and X is carbocyclyl e.g. heterocyclyl optionally substituted with R 11 .
  • X is aryl, for example heteroaryl, or heterocyclyl optionally substituted with R 11 .
  • W is aryl optionally substituted with R 11 and X is C 1-6 alkyl, e.g. CH 2 .
  • R 1 and R 2 are joined with N to form a saturated five to seven membered protonatable N-containing heterocycle, for example piperidine, azepane or azocane, optionally substituted with one or more R 12 .
  • a saturated five to seven membered protonatable N-containing heterocycle for example piperidine, azepane or azocane, optionally substituted with one or more R 12 .
  • R 1 or R 2 is an amine.
  • R 1 and R 2 wherein one of R 1 or R 2 is an amine, are joined with N to form a protonatable N containing heterocycle for example piperazine, optionally substituted with one or more R 12 .
  • R 4 is selected from hydrogen or C- ⁇ -6 alkyl optionally substituted with halogen, cyano, amino, hydroxy, Ci -6 alkyl and Ci -6 alkoxy or carbocyclyl, for example cycloalkyl or aryl. The inventors have found that substitution of the sulphonamide nitrogen atom enhances penetration of the compounds into the mouse CNS.
  • R 4 is Ci -6 alkyl e.g. methyl or Ci- 6 alkyl substituted with fluoro e.g. monofluoroalkyl, difluoroalkyl or trifluoroalkyl.
  • R 5 is selected from hydrogen and Ci -6 alkyl e.g. methyl.
  • the invention further provides a compound of formula V
  • n, ring A, W, ring B, R 3 , R 4 , R 5 , p and q are as defined herein; t is 0, 1 , 2, 3, 4, 5 or 6; ring D is an optionally substituted nitrogen containing 6 or 7 membered heterocycle, for example piperidine, wherein each substitutable carbon or nitrogen in Ring D is optionally and independently substituted by one or more R 7 ; R 7 is independently selected from hydrogen, R 20 , hydrocarbyl (e.g.
  • Ci -6 alkyl, alkenyl, alkynyl.or haloalkyl) optionally substituted with R 20 , and -(CH 2 ) V - heterocyclyl optionally substituted with R 20 ; v is 0, 1 , 2, 3, 4, 5 or 6; wherein each R 20 is independently selected from halogen, trifluoromethyl, cyano, thio, nitro, oxo, NR 21 , -OR 21 , -SR 21 , -C(O)R 21 , -C(O)OR 21 , - OC(O)R 21 , -NR 21 COR 22 , -NR 21 CONR 22 2, -NR 21 COR 22 , -NR 21 CO 2 R 22 , -S(O)R 21 , -S(O) 2 R 21 , -SONR 21 2 , -NR 21 S(O) 2 R 22 ; -CSR 21 , -N(R 21 )R 22 , -
  • R 21 and R 22 are each independently selected from hydrogen or R 23 ;
  • R 23 is selected from hydrocarbyl (e.g. C 1-6 alkyl, alkenyl, alkynyl.or haloalkyl), carbocyclyl and -(CH 2 ) w -heterocyclyl, and each R 23 is optionally and independently substituted with one or more of halogen, cyano, amino, hydroxy, Ci -6 alkyl and Ci -6 alkoxy; w is O, 1 , 2, 3, 4, 5 or 6;
  • R 8 is selected from the list of optional substituents represented by the group R 4 .
  • R 8 is hydrogen or methyl.
  • R 8 is methyl.
  • W is C-i-s alkyl, in particular Ci -6 alkyl, optionally substituted with oxo.
  • ring D, E, n, R 3 , R 4 , R 5 , R 7 , R 8 , p, q and t are as defined herein; n' is 0,1 , 2, 3, 4, 5, 6, 7 or 8.
  • E is C.
  • the invention further provides a compound of formula Vl
  • ring D is an optionally substituted nitrogen containing 6 or 7 membered heterocycle, for example 1 ,4-piperazine, wherein each substitutable carbon or nitrogen in Ring D is optionally and independently substituted by one or more R 7 .
  • the invention provides a compound of formula (Vl) wherein W is cycloalkyl, for example heterocycloalkyl such as piperidinyl.
  • ring B is a benzene ring or pyridinyl.
  • the invention provides a compound of formula (Vl)(i)
  • n, n', ring D, E, R 3 , R 4 , R 5 , R 7 , R 8 , p, q and t are as defined herein.
  • E is C.
  • W is an optionally substituted aryl or heteroaryl group.
  • n, ring A, ring B, ring D, R 3 , R 4 , R 5 , R 7 , R 8 , p, q and t are as defined herein; u is 0, 1 , 2, 3, 4, 5 or 6; ring C is an optionally substituted cyclic group wherein each substitutable carbon or heteroatom in Ring C is optionally and independently substituted by one or more R 6 ; R 6 is independently selected from hydrogen, R 20 , hydrocarbyl (e.g.
  • R 23 is selected from hydrocarbyl (e.g. Ci -6 alkyl, alkenyl, alkynyl.or haloalkyl), carbocyclyl and -(CH 2 ) w -heterocyclyl, and each R 23 is optionally and independently substituted with one or more of halogen, cyano, amino, hydroxy, C-i- ⁇ alkyl and Ci_6 alkoxy; w is 0, 1 , 2, 3, 4, 5 or 6;
  • n' is 0,1 ,2, 3, 4, 5, 6, 7 or 8.
  • the invention provides a compound of formula Vll(i)
  • n, n', ring C, ring D, E, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , p, q, t and u are as defined herein.
  • E is C.
  • Ring C may be a carbocycle, for example aryl.
  • ring C may be a heterocycle for example heterocycloalkyl (e.g. piperidinyl) or heteroaryl.
  • ring C is aryl (e.g. phenyl) or heteroaryl (pyridinyl).
  • ring D is 6 or 7 membered heterocycle, for example, a 6 membered heterocycle.
  • ring D is a saturated heterocycle.
  • ring D may be an optionally substituted pyrrolidine, pyrazolidine, imidazolidine, piperidine or piperazine (e.g. 1,4-piperazine).
  • ring D may be an unsaturated heterocycle for example an optionally substituted pyyrole, pyrazole, imidazole, imidazoline, pyridine, pyrazine, pyrimidine or triazine.
  • ring D is an optionally substituted imidazole.
  • n, n', ring A, ring B, ring D, R 3 , R 4 , R 5 , R 7 , R 8 , p, q and t are as defined herein; G is independently selected from C and N. In one embodiment there is provided a compound of formula VIII wherein G is C. In an alternative embodiment there is provided a compound of formula VIII wherein G is N.
  • ring D is selected from piperidin-4-yl, 1- methyl piperidin-4-yl, piperidin-3-yl, 1 -methyl piperidin-3-yl, piperidin-2-yl, 1- methyl piperidin-2-yl, piperazine-4-yl, 1-methyl piperazine-4-yl, 1 ,4- homopiperazine-4-yl, 1-methy-1 ,4-homopiperazin-4-yl, 1-methyl pyrolidin-3-yl, 1- methyl pyrolidin-2-yl, imidazol-1-yl, imidazol-2-yl, quinuclidin-3-yl, quinuclidin-4-yl.
  • the invention further provides a compound of formula IX(a)
  • n, n', E 1 X, R 3 , R 4 , R 5 , p and q are as defined herein and wherein J is independently a nitrogen containing heterocycle, for example heteroaryl, or an amine.
  • E is C.
  • J may be selected from piperidin-4-yl, 1-methyl piperidin-4-yl, piperidin-3-yl, 1- methyl piperidin-3-yl, piperidin-2-yl, 1-methyl piperidin-2-yl, piperazine-4-yl, 1- methyl piperazine-4-yl, 1 ,4-homopiperazine-4-yl, 1-methy-1 ,4-homopiperazin-4-yl, 1-methyl pyrolidin-3-yl, 1-methyl pyrolidin-2-yl, imidazol-1-yl, imidazol-2-yl, quinuclidin-3-yl, quinuclidin-4-yl.
  • Alternatively J may be selected from -NH 2 , a secondary amine of formula -NHR and a tertiary amine of formula -NRR', where R and R' are independently O- ⁇ alkyl optionally substituted with halogen, cyano, amino, hydroxy, C1-6 alkyl and Ci-6 alkoxy or carbocyclyl, for example cycloalkyl or aryl
  • R 4 is Ci-e alkyl optionally substituted with halogen, cyano, amino, hydroxy, Ci- ⁇ alkyl and Ci-e alkoxy or carbocyclyl, for example cycloalkyl or aryl.
  • R 3 is chloro, fluoro or methyl.
  • n' is 0, 1 or 2.
  • X is oxygen or Ci-e alkyl e.g. Chb.
  • the present invention further provides a compound according to the invention which comprises the racemate, the S or the R enantiomer or a mixture thereof, of a compound according to the invention.
  • the compound is the S- enantiomer or the R-enantiomer.
  • Preferred examples of compounds of the invention include DDD85646, DDD86481 , DD99742, DDD99837, DDD100097, DDD100144, DDD100153, DDD100156, DDD100159, DDD100160, DDD100161 and DDD100868 as shown in Table 1.
  • compositions of the invention include DD99742, DDD100097, DDD100144, DDD100153 as shown in Table 1.
  • An alternative preferred example of a compound of the invention is DDD85646.
  • Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in a known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallisation, or by the formation of a salt if appropriate or possible under the circumstances.
  • compositions of the invention may be in the form of salts.
  • the salts may be pharmaceutically acceptable salts.
  • the pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • the disclosure thus includes pharmaceutically-acceptable salts of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g. from inorganic or organic acids or bases.
  • acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3- phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, tosylate,
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N- methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl
  • diamyl sulfates long chain halides
  • the invention includes prodrugs for the active pharmaceutical species of the invention, for example in which one or more functional groups are protected or derivatised but can be converted in vivo to the functional group, as in the case of esters of carboxylic acids convertible in vivo to the free acid, or in the case of protected amines, to the free amino group.
  • prodrug represents in particular compounds which are rapidly transformed in vivo to the parent compound, for example, by hydrolysis in blood.
  • metabolic activations of prodrugs are nucleotide activation, phosphorylation activation and decarboxylation activation.
  • the compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. All diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means (e.g. HPLC, chromatography over silica).
  • HPLC chromatography over silica
  • the disclosure therefore includes all variant forms of the defined compounds, for example any tautomer or any pharmaceutically acceptable salt, ester, acid or other variant of the defined compounds and their tautomers as well as substances which, upon administration, are capable of providing directly or indirectly a compound as defined above or providing a species which is capable of existing in equilibrium with such a compound.
  • the compounds of the invention in free form or in pharmaceutically acceptable salt form possess pharmacological activity. They are therefore intended for use as a pharmaceutical. In particular they inhibit N-myristoyl transferase activity.
  • the compounds of the invention will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, by any other parenteral route, as an oral or nasal spray or via inhalation
  • the compounds may be administered in the form of pharmaceutical preparations comprising prodrug or active compound either as a free compound or, for example, a pharmaceutically acceptable non-toxic organic or inorganic acid or base addition salt, in a pharmaceutically acceptable dosage form.
  • the compositions may be administered at varying doses.
  • the pharmaceutical compounds of the invention may be administered orally or parenterally ("parenterally” as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion) to a host to obtain an inhibitory effect.
  • parenterally refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion
  • parenterally refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion
  • parenterally refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion
  • the compounds may be administered alone or as compositions in combination with pharmaceutically acceptable diluents, excipients or carriers.
  • Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration.
  • the selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses.
  • the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day.
  • a suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day.
  • compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0 and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. The dosage regimen may be adjusted to provide the optimal therapeutic response.
  • a pharmaceutical composition including a compound of the invention, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • compositions of this invention for parenteral injection suitably comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol or phenol sorbic acid. It may also be desirable to include isotonic agents such as sugars or sodium chloride, for example. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents (for example aluminum monostearate and gelatin) which delay absorption.
  • adjuvants such as preservative, wetting agents, emulsifying agents and dispersing agents.
  • Injectable depot forms are suitably made by forming microencapsule matrices of the drug in biodegradable polymers, for example polylactide-polyglycolide.
  • the rate of drug release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations may also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is typically mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or one or more: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate;
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycol, for example.
  • oral formulations contain a dissolution aid.
  • the dissolution aid is not limited as to its identity so long as it is pharmaceutically acceptable. Examples include nonionic surface active agents, such as sucrose fatty acid esters, glycerol fatty acid esters, sorbitan fatty acid esters (e.g.
  • sorbitan trioleate polyethylene glycol, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, methoxypolyoxyethylene alkyl ethers, polyoxyethylene alkylphenyl ethers, polyethylene glycol fatty acid esters, polyoxyethylene alkylamines, polyoxyethylene alkyl thioethers, polyoxyethylene polyoxypropylene copolymers, polyoxyethylene glycerol fatty acid esters, pentaerythritol fatty acid esters, propylene glycol monofatty acid esters, polyoxyethylene propylene glycol monofatty acid esters, polyoxyethylene sorbitol fatty acid esters, fatty acid alkylolamides, and alkylamine oxides; bile acid and salts thereof (e.g.,
  • ionic surface active agents such as sodium laurylsulfate, fatty acid soaps, alkylsulfonates, alkylphosphates, ether phosphates, fatty acid salts of basic amino acids; triethanolamine soap, and alkyl quaternary ammonium salts; and amphoteric surface active agents, such as betaines and aminocarboxylic acid salts.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, and/or in delayed fashion. Examples of embedding compositions include polymeric substances and waxes.
  • the active compounds may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • the active compounds may be in finely divided form, for example it may be micronised.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
  • inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol
  • the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth and mixtures thereof.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolisable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilisers, preservatives, excipients and the like.
  • the preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic.
  • Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which may be required.
  • Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the compounds of the invention may be orally active, have rapid onset of activity and low toxicity.
  • the compounds of the invention may have the advantage that they are more efficacious, less toxic, longer acting, have a broader range of activity, more potent, produce fewer side effects, more easily absorbed than, or have other useful pharmacological properties over, compounds known in the prior art.
  • NMT related diseases or disorders include but are not limited to hyperproliferative disorders, for example cancer, microbial infections, neurological diseases/disorders and diabetes and associated conditions.
  • cancer refers to cells having the capacity for autonomous growth, i.e., an abnormal state or condition characterized by rapidly proliferating cell growth.
  • the term is meant to include all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness.
  • cancer includes malignancies of the various organ systems, such as those affecting, for example, lung, breast, thyroid, lymphoid, gastrointestinal, and genito-urinary tract, as well as adenocarcinomas which include malignancies such as most colon cancers, renal-cell carcinoma, prostate cancer and/or testicular tumours, non-small cell carcinoma of the lung, cancer of the small intestine and cancer of the esophagus.
  • carcinoma is art recognized and refers to malignancies of epithelial or endocrine tissues including respiratory system carcinomas, gastrointestinal system carcinomas, genitourinary system carcinomas, testicular carcinomas, breast carcinomas, prostatic carcinomas, endocrine system carcinomas, and melanomas.
  • exemplary carcinomas include those forming from tissue of the cervix, lung, prostate, breast, head and neck, colon and ovary.
  • carcinosarcoma also includes carcinosarcomas, e.g., which include malignant tumours composed of carcinomatous and sarcomatous tissues.
  • An "adenocarcinoma” refers to a carcinoma derived from glandular tissue or in which the tumor cells form recognizable glandular structures.
  • the term “sarcoma” is art recognized and refers to malignant tumors of mesenchymal derivation. Further types of cancer include leukaemia, skin, intracranial and brain cancer.
  • microbial infection is meant an infection caused by a bacterium, parasite, protozoa, virus or fungus including yeast.
  • a “pathogen” is generally defined as any disease-causing organism.
  • a parasitic pathogen may be derived from a parasite selected from, but not limited to, the group consisting of Trypanosoma spp. (e.g. T. cruzi, T. brucei, T. congolense), Leishmania spp. (e.g. L. major, L. donovani, L. braziliensis), Giardia spp., Trichomonas spp. (e.g. Tr. vaginalis), Entamoeba spp. (e.g. E. histolytica), Naegleria spp., Acanthamoeba spp. (e.g. A. castelleni), Schistosoma spp. (e.g. S.
  • Trypanosoma spp. e.g. T. cruzi, T. brucei, T. congolense
  • Leishmania spp. e.g. L. major, L. donovani, L. braziliensis
  • Plasmodium spp. e.g. P. falciparum
  • Crytosporidium spp. lsospora spp.
  • Balantidium spp. Loa Loa
  • Ascaris lumbricoides Dirofilaria immitis
  • Toxoplasma ssp. e.g To. gondii
  • Onchocerca spp. e.g. O. volualno).
  • a viral pathogen may be derived from a virus selected from, but not limited to, the group consisting of: Human Immunodeficiency Virus (HIV1 & 2); Human T Cell Leukaemia Virus (HTLV 1 & 2); Ebola virus; human papilloma virus (e.g. HPV-2, HPV-5, HPV-8 HPV-16, HPV-18, HPV-31 , HPV-33, HPV-52, HPV-54 and HPV- 56); papovavirus; rhinovirus; poliovirus; herpesvirus; adenovirus; Epstein Barr virus; influenza virus, hepatitis B and C viruses, Variola virus, rotavirus or SARS coronavirus.
  • HCV1 & 2 Human Immunodeficiency Virus
  • HTLV 1 & 2 Human T Cell Leukaemia Virus
  • Ebola virus human papilloma virus (e.g. HPV-2, HPV-5, HPV-8 HPV-16, HPV-18,
  • a fungal pathogen may be derived from a fungus (including yeast) selected from, but not limited to, the genera Candida spp., (e.g. C.albicans, C. tropicalis), Aspergillus spp. (e.g. A. fumigatus), Cryptococcus spp. (e.g. Cryptococcus neoformans), and Saccharomyces spp. (e.g. Saccharomyces cerevisiae), Pneumocystis spp. (e.g. Pneumocystis carinii).
  • Candida spp. e.g. C.albicans, C. tropicalis
  • Aspergillus spp. e.g. A. fumigatus
  • Cryptococcus spp. e.g. Cryptococcus neoformans
  • Saccharomyces spp. e.g. Saccharomyces cerevisiae
  • neuropsychiatric disorders including Parkinson's Disease, Attention Deficit Hyperactivity Disorder (ADHD), depression (bipolar disorder) and schizophrenia and addiction
  • neurodegenerative disorders e.g. Alzheimer's disease, Tourette Syndrome, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, senile chorea, Sydenham's chorea, autism, head and spinal cord trauma, acute and chromic pain, epilepsy and seizures, dementia, distonia, tremor, autism, cerebral ischemia and neuronal cell death) and disorders linked to apoptosis (particularly neuronal apoptosis).
  • ADHD Attention Deficit Hyperactivity Disorder
  • depression depression
  • schizophrenia and addiction neurodegenerative disorders
  • Alzheimer's disease e.g. Alzheimer's disease, Tourette Syndrome, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, senile chorea, Sydenham's chorea, autism, head and spinal cord trauma, acute and chromic pain, epilepsy and seizures
  • the invention provides the use of a compound of the invention, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a NMT related disease or disorder.
  • the NMT related disease or disorder is cancer.
  • the compounds of the invention may be useful in the therapy of a variety of cancer including, but not limited to, prostate, breast, brain (e.g. glioma), gallbladder, colon, ovarian and oral (e.g. squamous cell) cancer or leukaemia.
  • the NMT related disease or disorder is a microbial infection for example a parasite, viral or fungal infection.
  • the parasite infection may be caused by Trypanosoma spp. (e.g. Trypanosoma cruzi, Trypansosoma brucei) or Leishmania spp. (e.g. L. major, L donovani) or Plasmodium spp. (e.g. P. falciparum).
  • the viral infection may be caused by HIV e.g. HIV1 or HIV2 or hepatitis B.
  • the fungal infection may be caused by a fungus selected from the group consisting of Candida albicans, Aspergillus Fumigatus, Pnemocystis carinii and Cryptococcus neoformans.
  • the microbial infection may include Leishmaniasis, Trypanosomiasis, Malaria, (Invasive) Aspergillosis, Candidiasis, Pneumocystis pneumonia and Cryptococcosis.
  • the NMT related disease or disorder is a neurological disease or disorder for example epilepsy or Alzheimer's disease.
  • the NMT related disease or disorder is diabetes, ischemia or osteoporosis.
  • the invention further provides a method of treating a NMT related disease or disorder in a subject which method comprises administering to said subject a therapeutically effective amount of a compound, or pharmaceutically acceptable salt thereof, or composition of the invention.
  • a subject is a mammal for example a human.
  • the compounds of the invention, or pharmaceutically acceptable salts thereof, may be administered in combination with a chemotherapeutic agent.
  • the invention provides a method of increasing the efficacy of a chemotherapeutic agent in a mammal having cancer, said method comprising administering to said mammal an effective amount of a compound of the invention or pharmaceutically acceptable salt thereof.
  • the invention provides a method of inhibiting the activity of one or more NMT (NMT1 and NMT2), said method comprising contacting one or more NMT with an effective amount of the compound of the invention.
  • the method may be an in vitro method.
  • the method may be an in vivo method.
  • treatment refers to clinical intervention in an attempt to alter the natural course of the individual or cell being treated, and may be performed either for prophylaxis or during the course of clinical pathology. Desirable effects include preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, lowering the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.
  • treatment as used herein is intended to include the treatment and prevention of the indicated conditions/disorders
  • a package or kit of parts comprising: (1) a compound, or pharmaceutically acceptable salt thereof, as described herein; together with (2) instructions to use said compound or salt in a method described herein.
  • the package defined herein may comprise more than one dosage unit, in order to provide for repeat dosing. If more than one dosage unit is present, such units may be the same, or may be different in terms of the dose of active agent composition and/or physical form. ;
  • a diluent for example an organic solvent e.g. dichloromethane or chloroform
  • a base for example an organic amine e.g. DIPEA, triethylamine etc. but preferentially pyridine, at a temperature in the range of 0-150 0 C.
  • the starting materials of formula (Xl), being derived from amine-bearing heterocycles such as pyridine, isoxazole and pyrazole may be prepared by methods analogous to those described in the accompanying examples or by standard methods well known in the art (Labeeuw, O. et al. Tett. Asymm., 2004, 15, 1899-1908 and Blay, G. et al. Tetrahedron, 2006, 62, 8069-8076).
  • compounds of formula (XIII) may be prepared by reacting an appropriately substituted aryl or heteroaryl halide with intermediate (XIV), where B(OR) 2 is typically -B(OH) 2 or any suitably reactive ester derivative thereof, which itself can be prepared from intermediate (XII) by an appropriate boronation reaction with a boronating reagent e.g. bispinacolatodiboron or pinacolborane, according to the method of Murata et al. (Murata, M; Oyama, T.;Watanabe, S; Masuda, Y., J. Org. Chem. 2000, 65, 164-168).
  • a boronating reagent e.g. bispinacolatodiboron or pinacolborane
  • a compound of formula (XIII) to a compound of formula (XVII) can also be effected via a five step process which comprises (i) reaction of intermediate (XII) with a suitably protected alcohol- bearing alkyne, for example tetrahydro-2-(2-propynyloxy)-2H-pyran; (ii) catalytic reduction of the alkyne with a suitable reducing agent; (iii) deprotection of the alcohol by treatment with HCI in a suitable protic solvent, such as methanol; (iv) conversion of the alcohol to a suitably reactive leaving group such as halo, e.g.
  • a strong base typically sodium hydride
  • a base such as sodium carbonate, potassium carbonate or caesium carbonate may be used, in which case the reaction may be performed in DMF at elevated temperature.
  • a reducing agent such as sodium cyanoborohydride
  • a compound of formula (XIII) wherein (R 6 ) u represents a hydroxyl group in the ortho-, meta-, or para- position may be converted to the corresponding compound wherein (R 6 ) u represents an imidazole or substituted imidazole, e.g.
  • a compound of formula (XVIII) may be converted to a compound of formula (XIX), by treatment with a primary or secondary cyclic or acyclic amine in a solvent such as ethanol at elevated temperature, such as 15O 0 C.
  • a primary or secondary cyclic or acyclic amine in a solvent such as ethanol at elevated temperature, such as 15O 0 C.
  • the transformation can be effected by reaction of an amine in the presence of a transition metal catalyst, e.g. palladium, and a strong base according to the methods described by Buchwald et al. (Wolf, J. P.; Buchwald, S.L.i J. Org. Chem., 2000, 65, 1158).
  • a compound of formula (XX) may be converted to a compound of the invention, under analogous conditions.
  • a compound of formula (XXI), wherein RX' represents a suitable leaving group, such as chloro or bromo or methanesulphonyl or para-toluenesulphonyl, may be converted to a compound of formula (XXI), wherein RX' represents -
  • NRaRb by treatment with an amine of formula HNRaRb under conditions which employ a solvent e.g. DMF, DMSO or ethanol, and an inorganic or organic base e.g. NEt 3 , DIPEA, potassium carbonate or sodium carbonate, as examples, at a temperature in the range of 0 to 17O 0 C.
  • a solvent e.g. DMF, DMSO or ethanol
  • an inorganic or organic base e.g. NEt 3 , DIPEA, potassium carbonate or sodium carbonate
  • a compound of formula (XXI), wherein RX' represents a suitable leaving group, such as chloro or bromo or methanesulphonyl or para- toluenesulphonyl may be converted to a compound of formula (XXI), wherein RX' represents -SRa, by treatment with a thiol-bearing compound of formula HSRa under analogous conditions as described.
  • a compound of formula (XXI), wherein RX' represents a suitable leaving group, such as chloro or bromo or methanesulphonyl or para- toluenesulphonyl may be converted to a compound of formula (XXI), wherein RX' represents -ORa, by treatment with an alcohol-bearing compound of formula HORa under analogous conditions as described.
  • a compound of formula (XXI), wherein RX' represents a suitable leaving group, such as chloro or bromo or methanesulphonyl or para-toluenesulphonyl may be converted to a compound of formula (XXI), wherein RX' represents -CHRaRb, by treatment with a compound of formula H 2 CRaRb, where Ra and/or Rb are functional groups capable of rendering the compound represented by H 2 C'RaRb as a carbon-based nucleophile following deprotonation under basic conditions.
  • Such compounds represented by HaCRaRb include, but are not limited to, dialkylmalonate and thiazolidine-1 ,3-dione, for example.
  • the compounds in accordance with this invention potently inhibit the activity of human, fungal and parasite NMT-1 and/or NMT-2.
  • N-myristoyl transferase is an enzyme that catalyses the addition of myristic acid from myristoyl coenzyme A to the N-terminal glycine residue of numerous substrate proteins and peptides with the subsequent release of coenzyme A.
  • 3 H- labelled myristoyl coenzyme A (GE Healthcare) can be used in the reaction to transfer 3 H-myristic acid to a biotinylated substrate peptide (GCGGSKVKPQPPQAK(Biotin)-Amide, Pepceuticals Inc).
  • the reaction can be measured by the subsequent binding of the labelled peptide to streptavidin- coated scintillation proximity assay (SPA) beads (GE Healthcare) and monitoring of ⁇ -particle excitation of the embedded scintillant.
  • SPA streptavidin- coated scintillation proximity assay
  • N-myristoyl transferase enzyme dissolved to a working concentration of 1OnM in assay buffer (3OmM Tris/HCI pH 7.4, 0.5mM EGTA 1 0.5 mM EDTA, 1.25 mM DTT, 0.1 % Triton X-100), was then added to columns 1 to 11 and 13 to 23 of the plates in a volume of 20ml. To columns 12 and 24, 20ml assay buffer was added to provide a no enzyme control. Following a 5 minute incubation at room temperature the substrates (GCGGSKVKPQPPQAK(Biotin)-Amide and myristoyl coenzyme A), dissolved in assay buffer, were added to all wells in a volume of 20ml to start the reaction.
  • 1OnM in assay buffer 3OmM Tris/HCI pH 7.4, 0.5mM EGTA 1 0.5 mM EDTA, 1.25 mM DTT, 0.1 % Triton X-100
  • the final concentrations of peptide and 3 H-myristoyl coenzyme A were 0.5mM and 125nM respectively and the specific activity of the radiolabel was 8 Ci/mmol. Plates were then incubated at room temperature for up to 50 minutes (dependant upon the period of linearity for the different enzyme species) before SPA beads, suspended to 1 mg/ml in a stop solution (20OmM Phosphoric Acid/NaOH pH 4, 75OmM MgCb), were added in a volume of 40ml. Plates were then read on a TopCount microplate luminometer and data analysed by calculating the percentage inhibition compared to the maximum and minimum assay controls. Concentration effect curves were fitted using non linear regression using XLFit 4.2 and IC 50 values determined.
  • In-vitro antitrypanosomal efficacy assay Measurement of the ability of the compounds to inhibit Trypanosome (T. brucei brucei) and Human (MRC5, human lung fibroblast cells) cell growth was performed using a modification of the cell viability assay previously described by Raz, B. et a/. (Acta. Trop. 68:139-14, 1997); Compounds were solubilised in DMSO at a top concentration of 1OmM and serially diluted in half log steps to achieve a range of final assay concentrations of 50 ⁇ M to 0.5nM. Compound at each concentration (200-fold final) was added to clear 96 well tissue culture plates in a volume of 1 ⁇ l.
  • test compounds were prepared from 1OmM DMSO stocks to give a final concentration range of 100 ⁇ M, 30 ⁇ M, 10 ⁇ M, 3 ⁇ M, 1 ⁇ M, 0.3 ⁇ M, 0.1 ⁇ M, 0.03 ⁇ M and 0.01 ⁇ M, with DMSO content constant at 1%.
  • Test compounds were incubated with the cells for 72h at 37°C, 5% CO 2 in a humidified atmosphere, iv) Alamar blue 10% (v/v) was then added and incubated for a further 6h, and fluorescent product detected using the BMG FLUOstar plate reader, v) Paclitaxel was used as a standard control inhibitor, vi) Data was analysed using a 4-parameter logistic equation in GraphPad Prism.
  • Figure 1 shows a Kaplan Meier survival plot for DDD85646 in an acute model of trypanosomiasis infection
  • INTERMEDIATE 4 (DDD88004) 4-Bromo-3,6-difluoro-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide Prepared from 2,5-difluoro-4-bromobenzenesulfonyl chloride (2g, 6.9mmol) and 4-amino- 1 ,3,5-trimethyl-1/-/-pyrazole (858mg, 6.9mmol) in pyridine (30ml) according to the method of intermediate 1 , to give the title compound as a pale yellow solid (1.9g, ⁇ .Ommol, 73%).
  • INTERMEDIATE 32 4-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-N-(1 ,3,5-trimethyl-1 H-pyrazol-4-yl)- benzenesulfonamide Prototypical procedure for conversion of an aryl halide to an aryl boronic ester;
  • N-(3,5-Dimethyl-isoxazol-4-yl)-4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)- benzenesulfonamide Prepared from the sulphonamide of intermediate 6 (1.01g, 3.06mmol) and bis- pinacolatodiboron (851 mg, 3.35mmol), potassium acetate (881 mg) and Pd(dppf)CI 2 .DCM (72mg) in oxygen-free dioxane (15ml) at 120 0 C for 2h according to the method of intermediate 32, to give the title compound as a tan coloured solid (661 mg, 1.75mmol, 57%).
  • 4-yl)-benzenesulfonamide Prepared from the sulphonamide of intermediate 2 (1.0g, 2.42mmol) and bis- pinacolatodiboron (700mg, 2.76mmol), potassium acetate (750mg) and Pd(dppf)CI 2 .DCM (60mg) in oxygen-free dioxane (12ml) at 120°C for 2h according to the method of intermediate 32, to give the title compound as an orange-brown solid (1.0g, 2.17mmol, 90%).
  • INTERMEDIATE 36 4-[3-(Tetrahydro-pyran-2-yloxy)-prop-1 -ynyl]-IM-(1 ,3,5-trimethyl-1 H-pyrazol-4-yl)- benzenesulfonamide Prototypical procedure for Sonogashira coupling of an an/I halide to an afkyne;
  • the thick suspension was allowed to warm to room temperature and stirred for 24 hours.
  • the reaction mixture was treated with saturated aqueous ammonium chloride (150ml) and the phases separated.
  • the aqueous phase was back-extracted with ethyl acetate (3 x 50 ml) and the combined organic phases were dried (Na 2 SO 4 ) and concentrated.
  • the residue was extracted with petroleum ether (2 x 100ml) and the combined extracts were concentrated to afford a yellow oil which was purified by chromatography (SiO 2 , 0-100%
  • METHOD 2 Alternatively this compound could be prepared by Suzuki reaction of the sulphonamide of intermediate 1 (500mg, 1.68mmol), 2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (581 mg, 2.0mmol), tribasic potassium phosphate (427mg, 2.0mmol), and Pd(dppf)CI 2 .DCM (50mg, 0.06mmol) in DMF (3.0ml) and water (0.75ml), according to the method of intermediate 11 , to give the title compound as an off-white powder (381 mg, 0.89mmol, 53%).
  • 1H-pyrazol-4-yl)-benzenesulfonamide Prepared by heating the chloropyridine of intermediate 12 (250mg, 0.58mmol) with 3- dimethylaminopiperidine (200 ⁇ l) in EtOH (1.5ml) at 155 0 C for 1h according to the method of DDD86213 to give the title compound as a white powder (150mg, 0.29mmol, 49%).
  • 1 H-pyrazol-4-yl)-benzenesulfonamide Prepared by heating the chloropyridine of intermediate 12 (250mg, 0.58mmol) with N-(2- pyridyl)ethylenediamine (200 ⁇ l) in EtOH (1.5ml) at 155°C for 1 h according to the method of DDD86213 to give the title compound as a white powder (111 mg, 0.2mmol, 35%).
  • -pyridin-4-yl)-benzenesulfonamide Prepared from the sulphonamide of intermediate 30 (79mg, 0.25mmol), 2-(1- piperazinyl)pyridine-4-boronic acid pinacol ester (80mg, 0.28mmol), tribasic potassium phosphate (60mg, 0.28mmol), and Pd(PPh 3 ) 4 (30mg, 0.026mmol) in DMF (1.6ml) and water (0.6ml), according to the method of intermediate 11 , to give the title compound as a white solid (46mg, 0.12mmol, 47%).
  • N-(3-isobutyl-1 ,5-dimethyl-1 H-pyrazol-4-yl)-4-(3-(1 -methylpipe ⁇ din-4- yl)propyl)benzenesulfonamide Prepared from 4-allyl-1 -methylpiperidine (2.18g, 15.6mmol) and the compound of intermediate 41 (2.Og, 5.2mmol) according to the method of compound DDD100096 to give the title compound as a white powder (1.84g, 4.12mmol, 79%).
  • the resulting solution was then transferred via cannula into a stirred mixture of the compound of intermediate 40 (300mg, 0.645mmol) and potassium phosphate (272mg, 1.28mmol) in DMF (2.5ml) and water (0.75ml) under argon. After bubbling argon through the reaction for 5min at rt Pd(PPh 3 ) 4 (20mg) was added, the reaction vessel sealed and then heated in a microwave at 6O 0 C for 30min. The reaction mixture was then concentrated in vacuo, diluted with DCM (50ml) and aqueous ammonia solution (50ml), the organic phase separated, washed with brine (2 x 25ml), dried (MgSO 4 ) and concentrated in vacuo.
  • Example DDD100798 The amine of Example DDD100798 (150mg, 0.31 mmol) was taken up in formic acid (10ml) and paraformaldehyde (92mg, 3.10mmol) added. The reaction mixture was heated at 85 0 C for 18h then allowed to cool and concentrated to dryness. The residue was basified with aqueous ammonia solution (20ml), extracted with DCM (20ml) and the organics concentrated in vacuo to give a gum which was subjected to chromatography (SiO 2 , 94:5:1 DCM: MeOH: saturated aqueous ammonia solution).
  • Enzyme activities are for T. brucei NMT. Where present, Human (/-/ ⁇ /NMT-1), Aspergillus fumigatus (>A/NMT) and Leishmania major (LmNMT) enzyme inhibition data are given in parentheses. Cellular activitites are for inhibition of T. brucei brucei (blood stream form, variant 221).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Obesity (AREA)
  • Virology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to N-heterocyclic sulphonamide compounds, in particular pyrazole sulphonamide compounds, and their use as N-myristoyl transferase inhibitors.

Description

N-MYRISTOYL TRANSFERASE INHIBITORS
Field of the Invention
The present invention relates to compounds and their use as N-myristoyl transferase inhibitors.
Background to the Invention
The modification of proteins by myristoylation is required for the subcellular targeting, protein conformation and biological activity of many important proteins in eukaryotic cells, including those required for signal transduction and regulatory functions important in cell growth (Towler et al. J Biol Chem 1987; 262:1030 - 6. 20: Wolven et al. MoI Biol Cell 1997; 8:1159 - 73.). The myristoylation reaction, the transfer of myristic acid from myristoyl-coenzyme A (CoA) to the amino groups of terminal glycine residues, is catalysed by the ubiquitously distributed enzyme N-myristoyl-CoA: protein, N-myristoyl transferase (NMT). The reaction requires only myristoyl-CoA and a protein containing a suitable peptide sequence, and occurs through an ordered Bi Bi mechanism. This modification occurs primarily as a cotranslational process (Wilcox et al. Science 1987, 238:1275 - 8. 22; Deichaite et al. MoI Cell Biol 1988; 8:4295 - 301), although myristoylation can also occur post-translationally (Pillai et al. Proc Natl Acad Sci USA 1987; 84:7654 - 8. 24: King et al. J Biol Chem 1989; 264:7772- 5.).
N-myristoyltransferase (NMT) has been shown to be essential in the kinetoplastid protozoan parasites, Leishmania, Trypanosoma brucei and Plasmodium- falciparum. The demonstration of essentiality by genetic studies in these parasites has been supported by limited chemical validation. Non-specific myristoyl CoA inhibitors inhibit T. brucei and Leishmania growth in culture. A screen of compounds developed as inhibitors of fungal NMT identified a number of inhibitors of both T. brucei NMT and T. brucei in culture. Screening of recombinant Plasmodium falciparum NMT has identified a series of benzothiazole analogues with IC5O values <50 μM, with selectivity over human NMT1. Two of compounds of the series when tested at a concentration of 10 μM against cultured parasites in vitro reduced parasitemia by >80%. (Bowyer et al., Biochemical Journal (2007), 408(2), 173-180.)
Two isozymes of the mammalian NMT enzymes, NMT1 and NMT2, have been cloned and share -77% identity (Giang DK, Cravatt BF. A second mammalian N- myristoyltransferase. J Biol Chem 1998; 273:6595 - 8.) with the majority of divergence occurring in the amino-terminal domains. Splice variants of NMT1 have also been observed in some cells. Possibly these amino-terminal variations allow differential cellular localization of the isozymes, thereby allowing either cotranslational ribosome-based or post-translational cytosol-based protein myristoylation. NMT1 and NMT2 have similar, but distinguishable, relative selectivity, as shown by an in vitro comparison of the activity of the isozymes on a limited panel of substrate peptides. (Giang and Cravatt, J Biol Chem 1998; 273:6595 - 8. 27; Aitken A, Biochem Soc Trans 1989; 17:871 - 5.).
The role of myristoylation is still being elucidated; however evidence of its involvement in many disease states, such as cancer (Selvakumar, P. et al., Progress in Lipid Res., 2006, (46), 1-36), epilepsy (Selvakhumar, P. et al., Biochem. Biophys Res. Comm. 2005, (335), 1132-1139), Alzheimer's disease, ischemia, diabetes, HIV (Shoji, S. et al., JP2006223173) and osteoporosis is growing. Cellular myristoylated proteins have diverse biological functions in oncogenesis and signal transduction. Examples include the catalytic subunit of cAMP4-dependent protein kinase, various tyrosine kinases (ppδOsrc, pp60yes, ppδδlck, pp59fyn/syn, and c-Abl), the α-subunit of calcineurin (Lakshmikuttyamma, A et al., Progress in Neurobiol. 2008, 84 (1), 77-84) the myristoylated alanine-rich C kinase substrate, and the α-subunit of several guanine nucleotide binding proteins and ADP ribosylation factors.
An increase in NMT activity and expression has been shown in a number of tumour types, suggesting inhibitors of NMT would be potential anti-cancer agents. In addition the Src family of tyrosine kinases (e.g., c-Src, Yes, and Fyn) are oncogenic proteins which require myristoylation in order for them to function in cells. Functionally characterization of the two NMT isozymes in human cells using unique small interfering RNAs (siRNA) for each isozyme were shown to decrease NMT1 or NMT2 protein levels by at least 90%. Knockdown of NMT1 inhibited cell replication associated with a loss of activation of c-Src and its target FAK. Depletion of either NMT isozyme induced apoptosis, with NMT2 having a 2.5-fold greater effect than NMT1. lntratumoral injection of siRNA for NMT1 or for both NMT1 and NMT2 inhibited tumour growth in vivo, whereas the same treatment with siRNA for NMT2 or negative control siRNA did not. Overall, the data indicate that NMT1 and NMT2 have only partially overlapping functions and that NMT1 is critical for tumour cell proliferation. (Ducker et al., MoI Cancer Res 2005; 3(8). August 2005).
Viruses and bacteria usually lack N-myristoyltransferases so consequently their proteins are processed by NMTs of their eukaryotic hosts. (Maurer-Stroh et al.,
Trends in Microbiology (2004), 12(4), 178-185.) For example, human N- myristoyltransferase (hNMT) catalyzes N-myristoylation of several HIV-1 proteins, including Pr160gag-pol, Pr55gag, the capsid protein p17 derived from proteolytic processing of gag, and neg. factor (nef). N-myristoylation of Pr160gag-pol and Pr55gag is required for viral replication. Reduction in the mRNA levels of human
NMT isoforms and NMT activities have been shown in the course of HIV-1 infection in the human T-cell line, CEM. In consequence, novel synthetic NMT inhibitors were significantly more cytotoxic to chronically HIV-1 infected T-cell line, CEM/LAV-1, compared to uninfected CEM cells. (Takamune et al., FEBS Letters (2002), 527(1-3), 138-142.)
Myristic acid analogues designed as alternative substrates for NMT have shown to inhibit the proliferation of HIV-1 (Bryant et al., Perspectives in Drug Discovery and Design (1993), 1(1), 193-209.; Devadas et al., Bioorganic & Medicinal Chemistry Letters (1993), 3(4), 779-84.) and Hepatitis B (Parang et al., Antiviral Research (1997), 34(3), 75-90.) In addition myristic acid analogues have been shown to inhibit HIV-1 (Adams et al.,Eur. Pat. Appl. (1992), 20 pp. EP 480901 A1) and Varicella Zoster virus replication (Gilbert et al., Antiviral Chemistry & Chemotherapy (1994), 5(3), 182-6.). NMT has been shown genetically to be essential for a number of fungal strains, such as Candida albicans (Weinberg et al., Molecular Microbiology (1995), 16(2), 241-50.), Saccharomyces cerevisiae, Cryptococcus neoformans (Lodge et al., PNAS USA (1994), 91(25), 12008-12.) and Aspergillus fumigatus (Cook, WJ et al., US Patent 20020025524 (2002), both in culture and animal models of infection.
Given the diverse role of myristoyl transferases and their association with a large variety of diseases and disorders, there is a need to find further myristoyl transferase inhibitors.
The present inventors have provided sulphonamide compounds which are inhibitors of N-myristoyl transferases.
Statements of the Invention
The present invention relates to a class of N-heterocyclic sulphonamides and to their use in therapy. More particularly, the invention provides a family of N- heteroarylsulphonamides which are substituted [in the meta- or para- position] by an optionally substituted amine-bearing moiety.
According to a first aspect of the invention there is provided a sulphonamide derivative comprising a sulphonamide group linking a N-heterocyclic head group and tail group via an aryl or heteroaryl linker attached to the tail wherein the tail includes a protonatable moiety such as a primary, secondary or tertiary alkylamine (or a protonatable heterocycle such as imidazole).
In a preferred aspect of the invention there is provided a compound of formula (I)
Figure imgf000006_0001
wherein
n is 0,1, 2, 3, 4, 5 or 6;
ring A, herein referred to as a "head" group, is an optionally substituted nitrogen containing aryl group wherein each substitutable carbon or nitrogen in Ring A is optionally and independently substituted by one or more R5 and wherein if Ring A contains an -NH- moiety that nitrogen may be optionally substituted by C-ι-6 alkyl (e.g. methyl); and wherein R4 and ring A together with the atoms to which they are attached may form a cyclic group.
ring B is an optionally substituted aryl or heteroaryl group wherein each substitutable carbon or heteroatom in Ring B is optionally and independently substituted by one or more R3;
W and X, one of which may be absent, are independently selected from R11, hydrocarbyl (e.g.C1-8 alkyl, alkenyl, alkynyl.or haloalkyl) optionally substituted with R11, and -(CH2)k-heterocyclyl optionally substituted with R12; k is 0, 1 , 2, 3, 4, 5 or 6;
R1, R2, R3, R4 and R5 are independently selected from hydrogen, R12, hydrocarbyl (e.g.Ci-6 alkyl, alkenyl, alkynyl.or haloalkyl) optionally substituted with R12, and - (CH2)ι-heterocyclyl optionally substituted with R12; wherein R1 and R2 taken together with the atoms to which they are attached may form a heterocycle, optionally substituted with one or more R12; wherein R1 and/or R2 taken together with W or X may form a heterocycle optionally substituted with one or more R12; and wherein one or more of R3 and R5 taken together with the atoms to which they are attached may form a carbocycle, for example heterocyclyl, optionally substituted with R12; I is 0, 1 , 2, 3, 4, 5 or 6;
wherein each R11 and R12 is independently selected from halogen, trifluoromethyl, cyano, thio, nitro, oxo, =NR13, -OR13, -SR13, -C(O)R13, -
C(O)OR13, -OC(O)R13, -NR13COR14, -NR13CONR13 2l -NR13COR14, - NR13CO2R14, -S(O)R13, -S(O)2R13, -SONR13 2, -NR13S(O)2R14; -CSR13, -N(R13)R14, -C(O)N(R13)R14, -SO2N(R13)R14 and R15;
wherein R13 and R14 are each independently selected from hydrogen or
R15;
wherein R15 is selected from hydrocarbyl (e.g.C-ι-6 alkyl, alkenyl, alkynyl.or haloalkyl), carbocyclyl and -(CH2)m-heterocyclyl, and each R15 is optionally and independently substituted with one or more of halogen, cyano, amino, hydroxy, C-ι-6 alkyl or cycloalkyl and C-ι-6 alkoxy; m is O, 1, 2, 3, 4, 5 or 6;
p is O, 1 , 2, 3 or 4; wherein the values of R4 may be the same or different; q is 0, 1 , 2, 3 or 4; wherein the values of R5 may be the same or different;
or a pharmaceutically acceptable salt or pro-drug thereof.
According to a further aspect of the invention there is provided a sulphonamide derivative comprising a sulphonamide group linking a heteroaryl head group and an aryl or heteroaryl central group for use as a medicament.
In a second aspect of the invention there is provided a compound of formula (II) for use as a medicament:
Figure imgf000008_0001
(H)
wherein n, ring A, ring B, R3, R4, R5, p and q are as defined herein;
Y and Z, one or both of which may be absent, are independently selected from hydrogen, R16, hydrocarbyl (e.g.Ci-6 alkyl, alkenyl, alkynyl.or haloalkyl) optionally substituted with R16, and -(CH2)r-heterocyclyl optionally substituted with R16, wherein each R16 is independently selected from halogen, trifluoromethyl, cyano, thio, nitro, oxo, =NR17, -OR17, -SR17, -C(O)R17, -C(O)OR17, -OC(O)R17, - NR17COR18, -NR17CONR182, -NR17COR18, -NR17CO2R18, -S(O)R17, -S(O)2R17, - SONR17 2, -NR17S(O)2R18; -CSR17, -N(R17)R18, -C(O)N(R17)R18, -SO2N(R17)R18 and R19; r is O, 1 , 2, 3, 4, 5 or 6;
wherein R17 and R18 are each independently selected from hydrogen or R19;
wherein R19 is selected from hydrocarbyl (e.g.Ci-6 alkyl, alkenyl, alkynyl.or haloalkyl), carbocyclyl and -(CH2)s-heterocyclyl, and each R19 is optionally and independently substituted with one or more of halogen, cyano, amino, hydroxy, Ci-6 alkyl and Ci-6 alkoxy; s is O, 1, 2, 3, 4, 5 or 6; 8 or a pharmaceutically acceptable salt or pro-drug thereof.
Preferably Y is absent and Z is halogen e.g. Br or Cl. Preferably still, ring B is aryl e.g. a 6-membered aromatic ring including benzene.
n may be 0 or 1. Preferably n is 0.
The compounds of the invention can exist in different forms, such as free acids, free bases, esters and other prodrugs, salts and tautomers, for example, and the invention includes all variant forms of the compounds.
Hydrocarbyl
The term "hydrocarbyl" as used herein includes reference to moieties consisting exclusively of hydrogen and carbon atoms; such a moiety may comprise an aliphatic and/or an aromatic moiety. The moiety may comprise 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. Examples of hydrocarbyl groups include Ci-6 alkyl (e.g. Ci, C2, C3 or C4 alkyl, for example methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl); Ci-6 alkyl substituted by aryl (e.g. benzyl) or by cycloalkyl (e.g cyclopropylmethyl); cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl); alkenyl (e.g. 2- butenyl); alkynyl (e.g. 2-butynyl); aryl (e.g. phenyl, benzyl, naphthyl or fluorenyl) and the like.
Alkyl The terms "alkyl" and "Ci-6 alkyl" as used herein can be used interchangeably and include reference to a straight or branched chain alkyl moiety having 1 , 2, 3, 4, 5 or 6 carbon atoms. This term includes reference to groups such as methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, iso-butyl, sec-butyl or tert- butyl), pentyl, hexyl and the like. In particular, alkyl may have 1 , 2, 3 or 4 carbon atoms. Haloalkyl relates to an alkyl radical preferably having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms, substituted with one or more halide atoms for example CH2CH2Br, CF3 or CCI3.
Alkenyl The terms "alkenyl" and "C2-6 alkenyl" as used herein can be used interchangeably and include reference to a straight or branched chain alkyl moiety having 2, 3, 4, 5 or 6 carbon atoms and having, in addition, at least one double bond, of either E or Z stereochemistry where applicable. This term. includes reference to groups such as ethenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3- butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl and 3-hexenyl and the like.
Alkynyl The terms "alkynyl" and "C2-6 alkynyl" as used herein can be used interchangeably and include reference to a straight or branched chain alkyl moiety having 2, 3, 4, 5 or 6 carbon atoms and having, in addition, at least one triple bond. This term includes reference to groups such as ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 2-butynyi, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1- hexynyl, 2-hexynyl and 3-hexynyl and the like.
Alkoxy
The terms "alkoxy" and "Ci-6 alkoxy" as used herein can be used interchangeably and include reference to -O-alkyl, wherein alkyl is straight or branched chain and comprises 1, 2, 3, 4, 5 or 6 carbon atoms. In one class of embodiments, alkoxy has 1 , 2, 3 or 4 carbon atoms. This term includes reference to groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, hexoxy and the like.
Cycloalkyl
The term "cycloalkyl" as used herein includes reference to an alicyclic moiety having 3, 4, 5, 6, 7 or 8 carbon atoms. The group may be a bridged or polycyclic ring system. More often cycloalkyl groups are monocyclic. This term includes reference to groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[2.2.2]octyl and the like.
Aryl
The term "aryl" as used herein includes reference to an aromatic ring system comprising 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring carbon atoms. Aryl is often phenyl but may be a polycyclic ring system, having two or more rings, at least one of which is aromatic. This term includes reference to groups such as phenyl, naphthyl, fluorenyl, azulenyl, indenyl, anthryl and the like.
Carbocyclyl
The term "carbocyclyl" as used herein includes reference to a saturated (e.g. cycloalkyl) or unsaturated (e.g. aryl) ring moiety having 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15 or 16 carbon ring atoms. In particular, carbocyclyl includes a 3- to 10-membered ring or ring system and, in particular, a 5- or 6-membered ring, which may be saturated or unsaturated. A carbocyclic moiety is, for example, selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbomyl, bicyclo[2.2.2]octyl, phenyl, benzyl, naphthyl, fluorenyl, azulenyl, indenyl, anthryl and the like.
Heterocyclyl
The term "heterocyclyl" as used herein includes reference to a saturated (e.g. heterocycloalkyl) or unsaturated (e.g. heteroaryl) heterocyclic ring moiety having from 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15 or 16 ring atoms, at least one of which is selected from nitrogen, oxygen, phosphorus, silicon and sulphur. In particular, heterocyclyl includes a 3- to 10-membered ring or ring system and more particularly a 5- or 6-or 7-membered ring, which may be saturated or unsaturated.
A heterocyclic moiety is, for example, selected from oxiranyl, azirinyl, 1 ,2- oxathiolanyl, imidazolyl, thienyl, furyl, tetrahydrofuryl, pyranyl, thiopyranyl, thianthrenyl, isobenzofuranyl, benzofuranyl, chromenyl, 2H-pyrrolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, py- ridyl, pyrazinyl, pyrimidinyl, piperidyl, piperazinyl, pyridazinyl, morpholinyl, thiomorpholinyl, especially thiomorpholino, indolizinyl, isoindolyl, 3H-indolyl, indolyl, benzimidazolyl, cumaryl, indazolyl, triazolyl, tetrazolyl, purinyl, 4H- quinolizinyl, isoquinolyl, quinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, octahydroisoquinolyl, benzofuranyl, dibenzofuranyl, benzothiophenyl, dibenzothiophenyl, phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, furazanyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromenyl, isochromanyl, chromanyl and the like.
Heterocycloalkyl
The term "heterocycloalkyl" as used herein includes reference to a saturated heterocyclic moiety having 3, 4, 5, 6 or 7 ring carbon atoms and 1 , 2, 3, 4 or 5 ring heteroatoms selected from nitrogen, oxygen, phosphorus and sulphur. The group may be a polycyclic ring system but more often is monocyclic. This term includes reference to groups such as azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxiranyl, pyrazolidinyl, imidazolyl, indolizidinyl, piperazinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, quinolinidinyl and the like.
Heteroaryl The term "heteroaryl" as used herein includes reference to an aromatic heterocyclic ring system having 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15 or 16 ring atoms, at least one of which is selected from nitrogen, oxygen and sulphur. The group may be a polycyclic ring system, having two or more rings, at least one of which is aromatic, but is more often monocyclic. This term includes reference to groups such as pyrimidinyl, furanyl, benzo[b]thiophenyl, thiophenyl, pyrrolyl, imidazolyl, pyrrolidinyl, pyridinyl, benzo[b]furanyl, pyrazinyl, purinyl, indolyl, benzimidazolyl, quinolinyl, phenothiazinyl, triazinyl, phthalazinyl, 2H-chromenyl, oxazolyl, isoxazolyl, thiazolyl, isoindolyl, indazolyl, purinyl, isoquinolinyl, quinazolinyl, pteridinyl and the like.
Halogen
The term "halogen" as used herein includes reference to F, Cl, Br or I. In particular, halogen may be F or Cl.
Substituted
The term "substituted" as used herein in reference to a moiety means that one or more, especially up to 5, more especially 1 , 2 or 3, of the hydrogen atoms in said moiety are replaced independently of each other by the corresponding number of the described substituents. The term "optionally substituted" as used herein means substituted or unsubstituted.
It will, of course, be understood that substituents are only at positions where they are chemically possible, the person skilled in the art being able to decide (either experimentally or theoretically) without inappropriate effort whether a particular substitution is possible. For example, amino or hydroxy groups with free hydrogen may be unstable if bound to carbon atoms with unsaturated (e.g. olefinic) bonds. Additionally, it will of course be understood that the substituents described herein may themselves be substituted by any substituent, subject to the aforementioned restriction to appropriate substitutions as recognised by the skilled man.
Independently Where two or more moieties are described as being "each independently" selected from a list of atoms or groups, this means that the moieties may be the same or different. The identity of each moiety is therefore independent of the identities of the one or more other moieties.
Ring A is preferably an optionally substituted 5 or 6 membered nitrogen containing heteroaryl. For example, ring A may be an optionally substituted 5 membered nitrogen-containing heteroaryl including, but not limited to, optionally substituted pyrazole, imidazole, imidazoline, triazole or tetrazole. Alternatively ring A may be an optionally substituted 6 membered nitrogen-containing heteroaryl including, but not limited to, optionally substituted pyridine, 3 amino pyridine, 4 amino pyridine, pyridazine, pyrimidine, pyrazine, triazine and tetrazine.
Ring A may be comprise other ring heteroatoms in addition to N for example O or S. For example ring A may be optionally substituted isoxazole.
Preferably ring A is selected from optionally substituted pyrazole, pyridine or isoxazole. Preferably still ring A is optionally substituted pyrazole. Thus in a preferred aspect of the invention there is provided a compound of formula (III)
Figure imgf000014_0001
(III)
wherein n, ring B, W, X, R , R , Rό, R , Rr, p and q are as defined herein.
In a further preferred aspect of the invention there is provided a compound of formula (lll)(i)
Figure imgf000014_0002
("DO) wherein n, ring B, W1 X, R1, R2, R3, R4, p and q are as defined herein and R5a, R5b and R5c are independently selected from hydrogen, R12, hydrocarbyl (e.g.C-i-β alkyl, alkenyl, alkynyl,or haloalkyl) optionally substituted with R12, and -(CH2)ι- heterocyclyl optionally substituted with R12.
In one embodiment, there is provided a compound of formula (lll)(i) wherein R5a is C1-6 alkyl (e.g. methyl).
Preferably ring B is an optionally substituted 5 or 6 membered aryl (e.g. benzene) or heteroaryl wherein each substitutable carbon or heteroatom in ring B may be optionally and independently substituted by halogen for example selected from one or more of F, Cl and Br. Ring B may be a 5 membered aryl containing one or more heteroatoms selected from N, S and O. By way of example ring B may be thiophene. Alternatively ring B may be a 6 membered aryl containing one or more heteratoms selected from N, S and O. By way of example ring B may be a 6 membered nitrogen containing heteroaryl, for example pyridine.
Thus there may be provided a compound of formula IV
Figure imgf000015_0001
(IV) wherein n, ring A, W, X, R1, R2, R3, R4, R5, p and q are as defined herein; and E is independently selected from C and N.
In one embodiment the invention provides a compound of formula (IV) wherein E is N.
In another embodiment the invention provides a compound of formula (IV) wherein E is C.
In a preferred aspect of the invention there is provided a compound of formula (IV)O)
Figure imgf000016_0001
(IV)O)
wherein n, W, X, R1, R2, R3, R4, R5, p and q are as defined herein; and E is independently selected from C and N.
In a further preferred aspect of the invention there is provided a compound of formula (IV)(U)
Figure imgf000017_0001
(IV)(U)
wherein n, W, X, R1, R2, R4, R5, p and q are as defined herein; and wherein R3a, R3b, R3c and R3d are independently selected from hydrogen, R12, hydrocarbyl (e.g. Ci-6 alkyl, alkenyl, alkynyl,or haloalkyl) optionally substituted with R12, and - (CH2)ι-heterocyclyl optionally substituted with R12.
Preferably, R3a, R3b, R3c and R3d are independently selected from hydrogen, halogen (e.g. Cl or F) and Ci-6 alkyl or haloalkyl.
In a further preferred aspect of the invention there is provided a compound of formula (IV)(Ui)
Figure imgf000018_0001
(IV)(Mi)
Preferably R3a and/or R3b is halogen for example Cl or F.
In a preferred aspect of the invention W is absent and X is carbocyclyl e.g. heterocyclyl optionally substituted with R11. Preferably X is aryl, for example heteroaryl, or heterocyclyl optionally substituted with R11.
In one embodiment of the invention, W is aryl optionally substituted with R11 and X is C1-6 alkyl, e.g. CH2.
Preferably R1 and R2 are joined with N to form a saturated five to seven membered protonatable N-containing heterocycle, for example piperidine, azepane or azocane, optionally substituted with one or more R12.
Preferably at least one of R1 or R2 is an amine. Preferably still R1 and R2, wherein one of R1 or R2 is an amine, are joined with N to form a protonatable N containing heterocycle for example piperazine, optionally substituted with one or more R12. Preferably R4 is selected from hydrogen or C-ι-6 alkyl optionally substituted with halogen, cyano, amino, hydroxy, Ci-6 alkyl and Ci-6 alkoxy or carbocyclyl, for example cycloalkyl or aryl. The inventors have found that substitution of the sulphonamide nitrogen atom enhances penetration of the compounds into the mouse CNS. Thus, preferably still R4 is Ci-6 alkyl e.g. methyl or Ci-6 alkyl substituted with fluoro e.g. monofluoroalkyl, difluoroalkyl or trifluoroalkyl.
Preferably R5 is selected from hydrogen and Ci-6 alkyl e.g. methyl.
The invention further provides a compound of formula V
Figure imgf000019_0001
(V)
wherein n, ring A, W, ring B, R3, R4, R5, p and q are as defined herein; t is 0, 1 , 2, 3, 4, 5 or 6; ring D is an optionally substituted nitrogen containing 6 or 7 membered heterocycle, for example piperidine, wherein each substitutable carbon or nitrogen in Ring D is optionally and independently substituted by one or more R7; R7 is independently selected from hydrogen, R20, hydrocarbyl (e.g. Ci-6 alkyl, alkenyl, alkynyl.or haloalkyl) optionally substituted with R20, and -(CH2)V- heterocyclyl optionally substituted with R20; v is 0, 1 , 2, 3, 4, 5 or 6; wherein each R20 is independently selected from halogen, trifluoromethyl, cyano, thio, nitro, oxo, =NR21, -OR21, -SR21, -C(O)R21, -C(O)OR21, - OC(O)R21, -NR21COR22, -NR21CONR222, -NR21COR22, -NR21CO2R22, -S(O)R21, -S(O)2R21, -SONR21 2, -NR21S(O)2R22; -CSR21, -N(R21)R22, -C(O)N(R21)R22, -SO2N(R21)R22 and R23;
wherein R21 and R22 are each independently selected from hydrogen or R23;
wherein R23 is selected from hydrocarbyl (e.g. C1-6 alkyl, alkenyl, alkynyl.or haloalkyl), carbocyclyl and -(CH2)w-heterocyclyl, and each R23 is optionally and independently substituted with one or more of halogen, cyano, amino, hydroxy, Ci-6 alkyl and Ci-6 alkoxy; w is O, 1 , 2, 3, 4, 5 or 6;
R8 is selected from the list of optional substituents represented by the group R4.
Preferably R8 is hydrogen or methyl. Preferably still R8 is methyl.
Preferably W is C-i-s alkyl, in particular Ci-6 alkyl, optionally substituted with oxo.
In a preferred aspect of the invention there is provided a compound of formula (V)(O
Figure imgf000021_0001
(V)(O
wherein ring D, E, n, R3, R4, R5, R7, R8, p, q and t are as defined herein; n' is 0,1 , 2, 3, 4, 5, 6, 7 or 8. Preferably E is C.
The invention further provides a compound of formula Vl
Figure imgf000021_0002
(Vl) wherein n, ring A, W, ring B, R3, R4, R5, R7, R8, p, q and t are as defined herein; ring D is an optionally substituted nitrogen containing 6 or 7 membered heterocycle, for example 1 ,4-piperazine, wherein each substitutable carbon or nitrogen in Ring D is optionally and independently substituted by one or more R7.
In one embodiment the invention provides a compound of formula (Vl) wherein W is cycloalkyl, for example heterocycloalkyl such as piperidinyl.
In one embodiment of the invention there is provided a compound of formula Vl wherein W is Ci-6 alkyl for example propyl.
Preferably ring B is a benzene ring or pyridinyl. Thus, in a preferred aspect the invention provides a compound of formula (Vl)(i)
Figure imgf000022_0001
R8 (VI)(O
wherein n, n', ring D, E, R3, R4, R5, R7, R8, p, q and t are as defined herein. Preferably E is C. In a preferred compound of the invention W is an optionally substituted aryl or heteroaryl group. Thus in a further preferred aspect of the invention there is provided a compound of formula VII
Figure imgf000023_0001
R8
(VII)
wherein n, ring A, ring B, ring D, R3, R4, R5, R7, R8, p, q and t are as defined herein; u is 0, 1 , 2, 3, 4, 5 or 6; ring C is an optionally substituted cyclic group wherein each substitutable carbon or heteroatom in Ring C is optionally and independently substituted by one or more R6; R6 is independently selected from hydrogen, R20, hydrocarbyl (e.g. Ci-6 alkyl, alkenyl, alkynyl, or haloalkyl) optionally substituted with R20, and -(CH2)v-heterocyclyl optionally substituted with R20; v is O1 1 , 2, 3, 4, 5 or 6;
wherein each R20 is independently selected from halogen, trifluoromethyl, cyano, thio, nitro, oxo, =NR21, -OR21, -SR21, -C(O)R21, -C(O)OR21, - OC(O)R21, -S(O)R21, -S(O)2R21, -N(R21)R22, -C(O)N(R21)R22, - SO2N(R21)R22 and R23; wherein R21 and R22 are each independently selected from hydrogen or R23;
wherein R23 is selected from hydrocarbyl (e.g. Ci-6 alkyl, alkenyl, alkynyl.or haloalkyl), carbocyclyl and -(CH2)w-heterocyclyl, and each R23 is optionally and independently substituted with one or more of halogen, cyano, amino, hydroxy, C-i-β alkyl and Ci_6 alkoxy; w is 0, 1 , 2, 3, 4, 5 or 6;
n' is 0,1 ,2, 3, 4, 5, 6, 7 or 8.
In one embodiment of the invention there is provided a compound of formula VII wherein ring B and Ring C are aryl.
In a preferred aspect, the invention provides a compound of formula Vll(i)
Figure imgf000024_0001
(Vll)(i) wherein n, n', ring C, ring D, E, R3, R4, R5, R6, R7, R8, p, q, t and u are as defined herein. Preferably E is C.
Ring C may be a carbocycle, for example aryl. Alternatively ring C may be a heterocycle for example heterocycloalkyl (e.g. piperidinyl) or heteroaryl. Preferably ring C is aryl (e.g. phenyl) or heteroaryl (pyridinyl).
Preferably ring D is 6 or 7 membered heterocycle, for example, a 6 membered heterocycle. Preferably ring D is a saturated heterocycle. By way of example, ring D may be an optionally substituted pyrrolidine, pyrazolidine, imidazolidine, piperidine or piperazine (e.g. 1,4-piperazine). Alternatively, ring D may be an unsaturated heterocycle for example an optionally substituted pyyrole, pyrazole, imidazole, imidazoline, pyridine, pyrazine, pyrimidine or triazine. Preferably still, ring D is an optionally substituted imidazole.
Thus in a further preferred aspect of the invention there is provided a compound of formula VIII
Figure imgf000025_0001
(VIII)
wherein n, n', ring A, ring B, ring D, R3, R4, R5, R7, R8, p, q and t are as defined herein; G is independently selected from C and N. In one embodiment there is provided a compound of formula VIII wherein G is C. In an alternative embodiment there is provided a compound of formula VIII wherein G is N.
In a preferred aspect of the invention, ring D is selected from piperidin-4-yl, 1- methyl piperidin-4-yl, piperidin-3-yl, 1 -methyl piperidin-3-yl, piperidin-2-yl, 1- methyl piperidin-2-yl, piperazine-4-yl, 1-methyl piperazine-4-yl, 1 ,4- homopiperazine-4-yl, 1-methy-1 ,4-homopiperazin-4-yl, 1-methyl pyrolidin-3-yl, 1- methyl pyrolidin-2-yl, imidazol-1-yl, imidazol-2-yl, quinuclidin-3-yl, quinuclidin-4-yl.
The invention further provides a compound of formula IX(a)
Figure imgf000026_0001
(IX)
wherein n, n', E1 X, R3, R4, R5, p and q are as defined herein and wherein J is independently a nitrogen containing heterocycle, for example heteroaryl, or an amine. Preferably E is C.
J may be selected from piperidin-4-yl, 1-methyl piperidin-4-yl, piperidin-3-yl, 1- methyl piperidin-3-yl, piperidin-2-yl, 1-methyl piperidin-2-yl, piperazine-4-yl, 1- methyl piperazine-4-yl, 1 ,4-homopiperazine-4-yl, 1-methy-1 ,4-homopiperazin-4-yl, 1-methyl pyrolidin-3-yl, 1-methyl pyrolidin-2-yl, imidazol-1-yl, imidazol-2-yl, quinuclidin-3-yl, quinuclidin-4-yl. Alternatively J may be selected from -NH2, a secondary amine of formula -NHR and a tertiary amine of formula -NRR', where R and R' are independently O-β alkyl optionally substituted with halogen, cyano, amino, hydroxy, C1-6 alkyl and Ci-6 alkoxy or carbocyclyl, for example cycloalkyl or aryl
Preferably R4 is Ci-e alkyl optionally substituted with halogen, cyano, amino, hydroxy, Ci-β alkyl and Ci-e alkoxy or carbocyclyl, for example cycloalkyl or aryl. Preferably R3 is chloro, fluoro or methyl. Preferably n' is 0, 1 or 2. Preferably X is oxygen or Ci-e alkyl e.g. Chb.
The present invention further provides a compound according to the invention which comprises the racemate, the S or the R enantiomer or a mixture thereof, of a compound according to the invention. Preferably, the compound is the S- enantiomer or the R-enantiomer.
Illustrative, but non-limiting, examples of the compounds, including pharmaceutically acceptable salts thereof, of the present invention are shown in Table 1.
Preferred examples of compounds of the invention include DDD85646, DDD86481 , DD99742, DDD99837, DDD100097, DDD100144, DDD100153, DDD100156, DDD100159, DDD100160, DDD100161 and DDD100868 as shown in Table 1.
Further preferred examples of compounds of the invention include DD99742, DDD100097, DDD100144, DDD100153 as shown in Table 1. An alternative preferred example of a compound of the invention is DDD85646.
Several methods for preparing the compounds of the invention are illustrated in the Schemes shown in the Examples (starting materials are made according to procedures known in the art or as illustrated herein). Thus in a further aspect of the invention there is provided a process for the manufacture of any one or more of the compounds according to the first aspect of the invention. Thus the invention provides a process for the preparation of a compound of formula I comprising the reaction steps of Example 1.
Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in a known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallisation, or by the formation of a salt if appropriate or possible under the circumstances.
Compounds of the invention may be in the form of salts. In particular, the salts may be pharmaceutically acceptable salts. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., US, 1985, p. 1418, the disclosure of which is hereby incorporated by reference; see also Stahl et al, Eds, "Handbook of Pharmaceutical Salts Properties Selection and Use", Verlag Helvetica Chimica Acta and Wiley-VCH, 2002.
The disclosure thus includes pharmaceutically-acceptable salts of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. For example the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g. from inorganic or organic acids or bases. Examples of such acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3- phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, tosylate, and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N- methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
The invention includes prodrugs for the active pharmaceutical species of the invention, for example in which one or more functional groups are protected or derivatised but can be converted in vivo to the functional group, as in the case of esters of carboxylic acids convertible in vivo to the free acid, or in the case of protected amines, to the free amino group. The term "prodrug," as used herein, represents in particular compounds which are rapidly transformed in vivo to the parent compound, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; H Bundgaard, ed, Design of Prodrugs, Elsevier, 1985; and Judkins, et al. Synthetic Communications, 26(23), 4351-4367 (1996), each of which is incorporated herein by reference.
Also to be mentioned as metabolic activations of prodrugs are nucleotide activation, phosphorylation activation and decarboxylation activation. For additional information, see "The Organic Chemistry of Drug Design and Drug Action", R B Silverman (particularly Chapter 8, pages 497 to 546), incorporated herein by reference.
The use of protecting groups is fully described in 'Protective Groups in Organic Chemistry", edited by J W F McOmie, Plenum Press (1973), and 'Protective Groups in Organic Synthesis', 2nd edition, T W Greene & P G M Wutz, Wiley- lnterscience (1991).
Thus, it will be appreciated by those skilled in the art that, although protected derivatives of compounds of the disclosure may not possess pharmacological activity as such, they may be administered, for example parenterally or orally, and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives are therefore examples of "prodrugs".
All prodrugs of the described compounds are included within the scope of the disclosure.
Some groups mentioned herein (especially those containing heteroatoms and conjugated bonds) may exist in tautomeric forms and all these tautomers are included in the scope of the disclosure. More generally, many species may exist in equilibrium, as for example in the case of organic acids and their counterpart anions; a reference herein to a species accordingly includes reference to all equilibrium forms thereof.
The compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. All diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means (e.g. HPLC, chromatography over silica). All stereoisomers are included within the scope of the disclosure. Where a single enantiomer or diasteromer is disclosed, the disclosure also covers the other enantiomers or diastereomers, and also racemates; in this regard, particular reference is made to the specific compounds listed herein. Geometric isomers may also exist in the compounds of the present disclosure. The present disclosure contemplates the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond and designates such isomers as of the Z or E configuration, wherein the term "Z" represents substituents on the same side of the carbon-carbon double bond and the term "E" represents substituents on opposite sides of the carbon-carbon double bond.
The disclosure therefore includes all variant forms of the defined compounds, for example any tautomer or any pharmaceutically acceptable salt, ester, acid or other variant of the defined compounds and their tautomers as well as substances which, upon administration, are capable of providing directly or indirectly a compound as defined above or providing a species which is capable of existing in equilibrium with such a compound.
Pharmaceutical Formulations and Use
The compounds of the invention in free form or in pharmaceutically acceptable salt form possess pharmacological activity. They are therefore intended for use as a pharmaceutical. In particular they inhibit N-myristoyl transferase activity.
Where used in therapy, the compounds of the invention will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, by any other parenteral route, as an oral or nasal spray or via inhalation, The compounds may be administered in the form of pharmaceutical preparations comprising prodrug or active compound either as a free compound or, for example, a pharmaceutically acceptable non-toxic organic or inorganic acid or base addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated and the route of administration, the compositions may be administered at varying doses.
Typically, therefore, the pharmaceutical compounds of the invention may be administered orally or parenterally ("parenterally" as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion) to a host to obtain an inhibitory effect. In the case of larger animals, such as humans, the compounds may be administered alone or as compositions in combination with pharmaceutically acceptable diluents, excipients or carriers.
Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
In the treatment, prevention, control, amelioration, or reduction of risk of conditions which require inhibition of kinase activity, an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0 and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. The dosage regimen may be adjusted to provide the optimal therapeutic response. According to a further aspect of the invention there is thus provided a pharmaceutical composition including a compound of the invention, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
Pharmaceutical compositions of this invention for parenteral injection suitably comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol or phenol sorbic acid. It may also be desirable to include isotonic agents such as sugars or sodium chloride, for example. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents (for example aluminum monostearate and gelatin) which delay absorption.
In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are suitably made by forming microencapsule matrices of the drug in biodegradable polymers, for example polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations may also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is typically mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or one or more: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycol, for example.
Suitably, oral formulations contain a dissolution aid. The dissolution aid is not limited as to its identity so long as it is pharmaceutically acceptable. Examples include nonionic surface active agents, such as sucrose fatty acid esters, glycerol fatty acid esters, sorbitan fatty acid esters (e.g. sorbitan trioleate), polyethylene glycol, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, methoxypolyoxyethylene alkyl ethers, polyoxyethylene alkylphenyl ethers, polyethylene glycol fatty acid esters, polyoxyethylene alkylamines, polyoxyethylene alkyl thioethers, polyoxyethylene polyoxypropylene copolymers, polyoxyethylene glycerol fatty acid esters, pentaerythritol fatty acid esters, propylene glycol monofatty acid esters, polyoxyethylene propylene glycol monofatty acid esters, polyoxyethylene sorbitol fatty acid esters, fatty acid alkylolamides, and alkylamine oxides; bile acid and salts thereof (e.g. chenodeoxycholic acid, cholic acid, deoxycholic acid, dehydrocholic acid and salts thereof, and glycine or taurine conjugate thereof); ionic surface active agents, such as sodium laurylsulfate, fatty acid soaps, alkylsulfonates, alkylphosphates, ether phosphates, fatty acid salts of basic amino acids; triethanolamine soap, and alkyl quaternary ammonium salts; and amphoteric surface active agents, such as betaines and aminocarboxylic acid salts.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, and/or in delayed fashion. Examples of embedding compositions include polymeric substances and waxes.
The active compounds may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
The active compounds may be in finely divided form, for example it may be micronised.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof. Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents. Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth and mixtures thereof.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolisable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilisers, preservatives, excipients and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p 33 et seq. Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which may be required. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
Advantageously, the compounds of the invention may be orally active, have rapid onset of activity and low toxicity.
The compounds of the invention may have the advantage that they are more efficacious, less toxic, longer acting, have a broader range of activity, more potent, produce fewer side effects, more easily absorbed than, or have other useful pharmacological properties over, compounds known in the prior art.
Compounds of the invention may be useful in the therapy of a variety of diseases and conditions. In particular, compounds of the invention may be useful in the treatment or prevention of diseases or disorders which can be prevented, alleviated or treated by modulation/inhibition of N-myristoyl transferase (NMT) activity (referred to herein as NMT related diseases or disorders). Such NMT related diseases or disorders include but are not limited to hyperproliferative disorders, for example cancer, microbial infections, neurological diseases/disorders and diabetes and associated conditions.
As used herein, the term "cancer" refers to cells having the capacity for autonomous growth, i.e., an abnormal state or condition characterized by rapidly proliferating cell growth. The term is meant to include all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness. The term "cancer" includes malignancies of the various organ systems, such as those affecting, for example, lung, breast, thyroid, lymphoid, gastrointestinal, and genito-urinary tract, as well as adenocarcinomas which include malignancies such as most colon cancers, renal-cell carcinoma, prostate cancer and/or testicular tumours, non-small cell carcinoma of the lung, cancer of the small intestine and cancer of the esophagus. The term "carcinoma" is art recognized and refers to malignancies of epithelial or endocrine tissues including respiratory system carcinomas, gastrointestinal system carcinomas, genitourinary system carcinomas, testicular carcinomas, breast carcinomas, prostatic carcinomas, endocrine system carcinomas, and melanomas. Exemplary carcinomas include those forming from tissue of the cervix, lung, prostate, breast, head and neck, colon and ovary.
The term "carcinoma" also includes carcinosarcomas, e.g., which include malignant tumours composed of carcinomatous and sarcomatous tissues. An "adenocarcinoma" refers to a carcinoma derived from glandular tissue or in which the tumor cells form recognizable glandular structures. The term "sarcoma" is art recognized and refers to malignant tumors of mesenchymal derivation. Further types of cancer include leukaemia, skin, intracranial and brain cancer.
By "microbial infection" is meant an infection caused by a bacterium, parasite, protozoa, virus or fungus including yeast. A "pathogen" is generally defined as any disease-causing organism.
A parasitic pathogen may be derived from a parasite selected from, but not limited to, the group consisting of Trypanosoma spp. ( e.g. T. cruzi, T. brucei, T. congolense), Leishmania spp. (e.g. L. major, L. donovani, L. braziliensis), Giardia spp., Trichomonas spp. (e.g. Tr. vaginalis), Entamoeba spp. (e.g. E. histolytica), Naegleria spp., Acanthamoeba spp. (e.g. A. castelleni), Schistosoma spp. (e.g. S. mansoni, S. japonicam), Plasmodium spp. (e.g. P. falciparum), Crytosporidium spp., lsospora spp., Balantidium spp., Loa Loa, Ascaris lumbricoides, Dirofilaria immitis, Toxoplasma ssp. (e.g To. gondii), Onchocerca spp. (e.g. O. volualno).
A viral pathogen may be derived from a virus selected from, but not limited to, the group consisting of: Human Immunodeficiency Virus (HIV1 & 2); Human T Cell Leukaemia Virus (HTLV 1 & 2); Ebola virus; human papilloma virus (e.g. HPV-2, HPV-5, HPV-8 HPV-16, HPV-18, HPV-31 , HPV-33, HPV-52, HPV-54 and HPV- 56); papovavirus; rhinovirus; poliovirus; herpesvirus; adenovirus; Epstein Barr virus; influenza virus, hepatitis B and C viruses, Variola virus, rotavirus or SARS coronavirus.
A fungal pathogen may be derived from a fungus (including yeast) selected from, but not limited to, the genera Candida spp., (e.g. C.albicans, C. tropicalis), Aspergillus spp. (e.g. A. fumigatus), Cryptococcus spp. (e.g. Cryptococcus neoformans), and Saccharomyces spp. (e.g. Saccharomyces cerevisiae), Pneumocystis spp. (e.g. Pneumocystis carinii).
As used herein the "neurological diseases/disorder" may include neuropsychiatric disorders, including Parkinson's Disease, Attention Deficit Hyperactivity Disorder (ADHD), depression (bipolar disorder) and schizophrenia and addiction; neurodegenerative disorders (e.g. Alzheimer's disease, Tourette Syndrome, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, senile chorea, Sydenham's chorea, autism, head and spinal cord trauma, acute and chromic pain, epilepsy and seizures, dementia, distonia, tremor, autism, cerebral ischemia and neuronal cell death) and disorders linked to apoptosis (particularly neuronal apoptosis).
Thus the invention provides the use of a compound of the invention, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a NMT related disease or disorder.
In a preferred use according to the invention the NMT related disease or disorder is cancer. The compounds of the invention may be useful in the therapy of a variety of cancer including, but not limited to, prostate, breast, brain (e.g. glioma), gallbladder, colon, ovarian and oral (e.g. squamous cell) cancer or leukaemia.
In a further preferred use according to the invention the NMT related disease or disorder is a microbial infection for example a parasite, viral or fungal infection. By way of example the parasite infection may be caused by Trypanosoma spp. (e.g. Trypanosoma cruzi, Trypansosoma brucei) or Leishmania spp. (e.g. L. major, L donovani) or Plasmodium spp. (e.g. P. falciparum). The viral infection may be caused by HIV e.g. HIV1 or HIV2 or hepatitis B. The fungal infection may be caused by a fungus selected from the group consisting of Candida albicans, Aspergillus Fumigatus, Pnemocystis carinii and Cryptococcus neoformans. The microbial infection may include Leishmaniasis, Trypanosomiasis, Malaria, (Invasive) Aspergillosis, Candidiasis, Pneumocystis pneumonia and Cryptococcosis.
In a further use according to the invention the NMT related disease or disorder is a neurological disease or disorder for example epilepsy or Alzheimer's disease.
In a yet further use according to the invention the NMT related disease or disorder is diabetes, ischemia or osteoporosis.
The invention further provides a method of treating a NMT related disease or disorder in a subject which method comprises administering to said subject a therapeutically effective amount of a compound, or pharmaceutically acceptable salt thereof, or composition of the invention. Preferably the subject is a mammal for example a human.
The compounds of the invention, or pharmaceutically acceptable salts thereof, may be administered in combination with a chemotherapeutic agent. Thus in a further aspect the invention provides a method of increasing the efficacy of a chemotherapeutic agent in a mammal having cancer, said method comprising administering to said mammal an effective amount of a compound of the invention or pharmaceutically acceptable salt thereof.
lna further aspect the invention provides a method of inhibiting the activity of one or more NMT (NMT1 and NMT2), said method comprising contacting one or more NMT with an effective amount of the compound of the invention. The method may be an in vitro method. Alternatively the method may be an in vivo method.
As used herein, "treatment" refers to clinical intervention in an attempt to alter the natural course of the individual or cell being treated, and may be performed either for prophylaxis or during the course of clinical pathology. Desirable effects include preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, lowering the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.The term, "treatment" as used herein is intended to include the treatment and prevention of the indicated conditions/disorders
There is further provided a package or kit of parts comprising: (1) a compound, or pharmaceutically acceptable salt thereof, as described herein; together with (2) instructions to use said compound or salt in a method described herein.
The package defined herein may comprise more than one dosage unit, in order to provide for repeat dosing. If more than one dosage unit is present, such units may be the same, or may be different in terms of the dose of active agent composition and/or physical form. ;
Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of the words, for example "comprising" and "comprises", means "including but not limited to", and is not intended to (and does not) exclude other moieties, additives, components, integers or steps.
Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.
Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.
EXAMPLE 1 Materials and Methods The following abbreviations are used: Pd(dppf)CI2.DCM - [1 ,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium (II)- dichloromethane complex; THF - tetrahydrofuran,
EtOAc - ethyl acetate; DMF - N,N-dimethylformamide;
MeOH - methanol; Boc - t-butoxycarbonyl;
EtOH - ethanol; CHCI3 - chloroform;
DCM - dichloromethane; AcOH - acetic acid;
DIPEA - diisopropylethylamine; EtOH - ethanol;
Pyr - pyridine; Ar - aryl;
DMSO - dimethylsulphoxide; iPr - isopropyl;
Et 2O - diethylether; Me - methyl;
All NMR's were obtained either at 500MHz on a Bruker Avance Il spectrometer or at 300MHz on a Bruker DPX 300 spectrometer. All LCMS's were obtained using a Bruker Daltonics mass spectrometer in combination with an Agilent 1100 series high pressure liquid chromatograph. All Intermediates and Examples were named with the aid of Beilstein Autonom or were given names that seemed consistent with IUPAC convention.
General Methods of Synthesis of Compounds
The following is a description of a process for preparing a compound of the invention or a pharmaceutically acceptable salt thereof:
Figure imgf000042_0001
a) reacting a sulfonyl compound of formula (X) with an intermediate compound of formula (Xl) in which X' represents a leaving group for example halo, e.g. chloro, in the presence or absence of a diluent for example an organic solvent e.g. dichloromethane or chloroform and optionally in the presence of a base, for example an organic amine e.g. DIPEA, triethylamine etc. but preferentially pyridine, at a temperature in the range of 0-1500C. Where they are not commercially available, the starting materials of formula (Xl), being derived from amine-bearing heterocycles such as pyridine, isoxazole and pyrazole, may be prepared by methods analogous to those described in the accompanying examples or by standard methods well known in the art (Labeeuw, O. et al. Tett. Asymm., 2004, 15, 1899-1908 and Blay, G. et al. Tetrahedron, 2006, 62, 8069-8076).
Figure imgf000043_0001
Figure imgf000043_0002
b) reacting an intermediate sulphonamide compound of formula (XII) with an appropriately substituted aryl or heteroaryl boronic acid or a suitably reactive analogue therein, such as an aryl or heteroaryl pinacolboronic ester, in the presence of a metal catalyst, e.g. Pd or derivatives thereof, such as Pd(dppf)CI2.DCM or Pd(PPh3)4, and in a solvent such as DMF or THF, optionally with water as a co-solvent, and an organic or inorganic base such as triethylamine or potassium phosphate, and in the temperature range 0-170°C, to provide a compound of formula (XIII).
Where the appropriate boronic acids or boronic esters are not commercially available, compounds of formula (XIII) may be prepared by reacting an appropriately substituted aryl or heteroaryl halide with intermediate (XIV), where B(OR)2 is typically -B(OH)2 or any suitably reactive ester derivative thereof, which itself can be prepared from intermediate (XII) by an appropriate boronation reaction with a boronating reagent e.g. bispinacolatodiboron or pinacolborane, according to the method of Murata et al. (Murata, M; Oyama, T.;Watanabe, S; Masuda, Y., J. Org. Chem. 2000, 65, 164-168). c) reacting an intermediate compound of formula (XII) with an appropriately substituted alkyne of formula (XV) in the presence of a copper(l) halide e.g. copper(l) iodide, a metal catalyst e.g. Pd or derivatives thereof, such as Pd(PPh3)2CI2 or Pd(PPh3)4, and in a solvent such as DMF or THF, with an organic or inorganic base such as triethylamine, diisopropylamine or sodium acetate, and in the temperature range 0-1700C.
Figure imgf000045_0001
d) reacting an intermediate compound of formula (XII) with an appropriately substituted alkene in the presence of 9-borabicyclo[3.3.1]nonane and a metal catalyst e.g. tetrakis-triphenylphosphine palladium (O) or Pd(dppf)CI2.DCM and in a solvent such as DMF or THF, with an organic or inorganic base such as triethylamine, diisopropylamine or potassium phosphate, and in the temperature range 0-1700C, according to the methods described by Suzuki et al. (Miyaura, M.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.; Suzuki, A., J. Am. Chem. Soc, 1989, 111, 314-321) and Lynch et al. (Lynch, C. L. Bioorg. Med. Chem. Letts., 2003, -/3, 119-123).
It will be understood that certain compounds of the invention initially obtained from any of the above processes may, where appropriate, be elaborated into certain other compounds of the invention by techniques known to those skilled in the art. By way of example, the conversion of a compound of formula (XVI) to a compound of formula (XVII), where n'=1 or 2, can be effected by the use of a reducing agent, for example, hydrogen gas, in combination with a heterogeneous or homogeneous transition metal catalyst, such as Pd on charcoal, or Wilkinson's catalyst. Alternatively, transfer hydrogenation conditions can be employed to effect the same transformation, e.g. using tosylhydrazone or formic acid, or the use of a dissolving metal in a protic solvent i.e. lithium in liquid ammonia.
It will be understood that the conversion of a compound of formula (XIII) to a compound of formula (XVII) can also be effected via a five step process which comprises (i) reaction of intermediate (XII) with a suitably protected alcohol- bearing alkyne, for example tetrahydro-2-(2-propynyloxy)-2H-pyran; (ii) catalytic reduction of the alkyne with a suitable reducing agent; (iii) deprotection of the alcohol by treatment with HCI in a suitable protic solvent, such as methanol; (iv) conversion of the alcohol to a suitably reactive leaving group such as halo, e.g. chloro or bromo, or sulfonyl group, e.g. p-toluenesulfonyl or methanesulfonyl; and (v) displacement of the intermediate thereof obtained by an appropriately substituted amine e.g. piperazine or homopiperazine or a suitably substituted analogue thereof, in a solvent such as DMF or THF.
A compound of formula (XII), wherein R4 = H, can be converted into the corresponding compound of formula (XII), wherein R4 = (alkyl or substituted alkyl or substituted alkaryl etc..) by reaction with an appropriate alkyl or alkaryl halide, such as methyl iodide or benzyl bromide in the presence of a strong base, typically sodium hydride, in a solvent such as DMF. Alternatively a base such as sodium carbonate, potassium carbonate or caesium carbonate may be used, in which case the reaction may be performed in DMF at elevated temperature. A compound of formula (XII), wherein R4 = H, can be converted into the corresponding compound of formula (XII), wherein R4 = CF3CH2- or CHFaCH2-, by reaction with the appropriate fluoroalkyl trifluoromethanesulfonate in the presence of a base, typically potassium carbonate, in a solvent such as acetonitrile. A compound of formula (XII)1 wherein R4 = H, can be converted into the corresponding compound of formula (XII), wherein R4 = CHF2 by reaction with sodium chlorodifluoroacetate and potassium carbonate in acetonitrile.
Figure imgf000047_0001
A compound of formula (XIII), wherein (R6)u represents a -(CH2)n-formyl group in the ortho-, meta-, or para- position and n= 0,1 or 2, may be converted to the corresponding compound wherein (R6)u represents a -(CH2)n-NRR' moiety in the ortho-, meta-, or para- position and n= 0,1 or 2, wherein NRR' represents a substituted amine moiety such as dimethylamino-, diethylamino-, pyrolidine-1-yl-, piperazine-1-yl-, 4-methylpiperazine-1-yl- or related substituted analogues of piperazine, by reaction with an appropriate amine of formula HNRR' e.g. N- methylpiperazine in the presence of a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride.
A compound of formula (XIII) wherein (R6)u represents a -(CH2)n-alcohol group in the ortho-, meta-, or para- position and n= 0,1 or 2 may be converted to the corresponding compound wherein (R6)u represents a -(CH2)n-R in the ortho-, meta-, or para- position and n=1 or 2, where R is imidaz-1-yl or analogue thereof, e.g. 2-methyl-imidazol-1-yl, via a two step process which comprises; (i) conversion of the alcohol to a suitable leaving group, such as halo e.g. chloro, or sulfonyl e.g. methanesulfonyl or para-toluenesulfonyl; (ii) displacement of the intermediate thereof obtained by an appropriately substituted imidazole e.g. 2- methylimidazole or a suitably substituted analogue thereof, in a solvent such as DMF or THF, with a base such as potassium carbonate.
A compound of formula (XIII) wherein (R6)u represents a hydroxyl group in the ortho-, meta-, or para- position may be converted to the corresponding compound wherein (R6)u represents an imidazole or substituted imidazole, e.g. 1 H-imidazol- 2-yl, 1H-imidazol-4-yl, 1-methyl-imidazol-2~yl, 1-methyl-imidazol-4~yl and 1- methyl-imidazol-5-yl via a two step process which comprises; (i) conversion of the phenol to a trifluoromethanesulfonate by reaction with trifluoromethanesulphonic acid anhydride and triethylamine, in DCM at OdegC, followed by (ii) Suzuki reaction of the intermediate thereof obtained with an appropriately substituted bromo- or iodo- imidazole e.g. 1-methyl-2-bromoimidazole under conditions previously described herein.
(XVIII) (XIX)
Figure imgf000048_0001
Figure imgf000048_0002
A compound of formula (XVIII) may be converted to a compound of formula (XIX), by treatment with a primary or secondary cyclic or acyclic amine in a solvent such as ethanol at elevated temperature, such as 15O0C. Alternatively the transformation can be effected by reaction of an amine in the presence of a transition metal catalyst, e.g. palladium, and a strong base according to the methods described by Buchwald et al. (Wolf, J. P.; Buchwald, S.L.i J. Org. Chem., 2000, 65, 1158).
Figure imgf000049_0001
Likewise, a compound of formula (XX) may be converted to a compound of the invention, under analogous conditions.
Figure imgf000049_0002
A compound of formula (XXI), wherein RX' represents a suitable leaving group, such as chloro or bromo or methanesulphonyl or para-toluenesulphonyl, may be converted to a compound of formula (XXI), wherein RX' represents -
NRaRb, by treatment with an amine of formula HNRaRb under conditions which employ a solvent e.g. DMF, DMSO or ethanol, and an inorganic or organic base e.g. NEt3, DIPEA, potassium carbonate or sodium carbonate, as examples, at a temperature in the range of 0 to 17O0C.
Similarly, a compound of formula (XXI), wherein RX' represents a suitable leaving group, such as chloro or bromo or methanesulphonyl or para- toluenesulphonyl, may be converted to a compound of formula (XXI), wherein RX' represents -SRa, by treatment with a thiol-bearing compound of formula HSRa under analogous conditions as described.
Similarly, a compound of formula (XXI), wherein RX' represents a suitable leaving group, such as chloro or bromo or methanesulphonyl or para- toluenesulphonyl, may be converted to a compound of formula (XXI), wherein RX' represents -ORa, by treatment with an alcohol-bearing compound of formula HORa under analogous conditions as described. Similarly, a compound of formula (XXI), wherein RX' represents a suitable leaving group, such as chloro or bromo or methanesulphonyl or para-toluenesulphonyl, may be converted to a compound of formula (XXI), wherein RX' represents -CHRaRb, by treatment with a compound of formula H2CRaRb, where Ra and/or Rb are functional groups capable of rendering the compound represented by H2C'RaRb as a carbon-based nucleophile following deprotonation under basic conditions. Such compounds represented by HaCRaRb include, but are not limited to, dialkylmalonate and thiazolidine-1 ,3-dione, for example.
The compounds in accordance with this invention potently inhibit the activity of human, fungal and parasite NMT-1 and/or NMT-2.
Enzyme Inhibition Assay
Measurement of the ability of compounds to inhibit the NMT-1 and/or NMT-2 enzyme isoforms of human, trypanosome (T.brucei), leishmanial (L major) and fungal (A. fumigatus) species was performed using a modification of the scintillation proximity assay platform described previously by Georgopapadakou, N. H. et al. (22nd International Congress on Chemotherapy, 2001 , Abstract P16.001), as follows;
N-myristoyl transferase is an enzyme that catalyses the addition of myristic acid from myristoyl coenzyme A to the N-terminal glycine residue of numerous substrate proteins and peptides with the subsequent release of coenzyme A. 3H- labelled myristoyl coenzyme A (GE Healthcare) can be used in the reaction to transfer 3H-myristic acid to a biotinylated substrate peptide (GCGGSKVKPQPPQAK(Biotin)-Amide, Pepceuticals Inc). The reaction can be measured by the subsequent binding of the labelled peptide to streptavidin- coated scintillation proximity assay (SPA) beads (GE Healthcare) and monitoring of β-particle excitation of the embedded scintillant.
Compounds were solubilised in DMSO at a top concentration of 1OmM and serially diluted in half log steps to achieve a range of final assay concentrations of 100μM to 1nM. Compound at each concentration (100-fold final) was added to white 384 well plates in a volume of 0.5ml. Human , A. fumigatus, T.brucei or L. major N-myristoyl transferase enzyme, dissolved to a working concentration of 1OnM in assay buffer (3OmM Tris/HCI pH 7.4, 0.5mM EGTA1 0.5 mM EDTA, 1.25 mM DTT, 0.1 % Triton X-100), was then added to columns 1 to 11 and 13 to 23 of the plates in a volume of 20ml. To columns 12 and 24, 20ml assay buffer was added to provide a no enzyme control. Following a 5 minute incubation at room temperature the substrates (GCGGSKVKPQPPQAK(Biotin)-Amide and myristoyl coenzyme A), dissolved in assay buffer, were added to all wells in a volume of 20ml to start the reaction. The final concentrations of peptide and 3H-myristoyl coenzyme A were 0.5mM and 125nM respectively and the specific activity of the radiolabel was 8 Ci/mmol. Plates were then incubated at room temperature for up to 50 minutes (dependant upon the period of linearity for the different enzyme species) before SPA beads, suspended to 1 mg/ml in a stop solution (20OmM Phosphoric Acid/NaOH pH 4, 75OmM MgCb), were added in a volume of 40ml. Plates were then read on a TopCount microplate luminometer and data analysed by calculating the percentage inhibition compared to the maximum and minimum assay controls. Concentration effect curves were fitted using non linear regression using XLFit 4.2 and IC50 values determined.
In-vitro antitrypanosomal efficacy assay Measurement of the ability of the compounds to inhibit Trypanosome (T. brucei brucei) and Human (MRC5, human lung fibroblast cells) cell growth was performed using a modification of the cell viability assay previously described by Raz, B. et a/. (Acta. Trop. 68:139-14, 1997); Compounds were solubilised in DMSO at a top concentration of 1OmM and serially diluted in half log steps to achieve a range of final assay concentrations of 50μM to 0.5nM. Compound at each concentration (200-fold final) was added to clear 96 well tissue culture plates in a volume of 1μl. 2000 cells per well in relevant growth media (HMI-9 for T.brucei as described by Hurumi, H. et al. J. Parasitol. 75(6):985-989, 1989; MEM with10% FBS for MRC5) were then added to columns 1 to 11 of the plates in a volume of 199μl. To column 12, 200μl media was added to provide a no cells control. Plates were then incubated at 370C in an atmosphere of 5% CO2 for 69 hours, before the addition of 20μl of 500μM rezasurin solution, and a further incubation period of 4 hours. Plates were then read on a BioTek flxδOO fluorescent plate reader and percentage inhibition compared to the maximum and minimum assay controls. Concentration effect curves were fitted using non-linear regression using XLFit 4.2 and EC5O values determined.
In-vitro antiproliferative assay
The ability of test compounds to inhibit the proliferation of a panel of human cancer cell lines was determined using the following protocol; i) cells were seeded in 96-well plates at a cell density of 3000/well, and allowed to adhere overnight prior to addition of compound or vehicle control, ii) Test compounds were prepared from 1OmM DMSO stocks to give a final concentration range of 100μM, 30μM, 10μM, 3μM, 1 μM, 0.3μM, 0.1 μM, 0.03μM and 0.01 μM, with DMSO content constant at 1%. iii) Test compounds were incubated with the cells for 72h at 37°C, 5% CO2 in a humidified atmosphere, iv) Alamar blue 10% (v/v) was then added and incubated for a further 6h, and fluorescent product detected using the BMG FLUOstar plate reader, v) Paclitaxel was used as a standard control inhibitor, vi) Data was analysed using a 4-parameter logistic equation in GraphPad Prism.
The following Intermediates and Examples illustrate the preparation and properties of compounds according to the invention with reference to the following figure: Figure 1 shows a Kaplan Meier survival plot for DDD85646 in an acute model of trypanosomiasis infection
INTERMEDIATE 1 4-Bromo-N-(1 ,3,5-trimethyM H-pyrazoI-4-yI)-benzenesulfonamide
Prototypical procedure for preparation of a sulphonamide from an amine and a sulfonyl chloride;
4-Bromobenzene sulfonyl chloride (5.Og, 19.6mmol) was added portionwise to a stirred solution of 4~amino-1 ,3,5-trimethyl-1W-pyrazole (2.45g, 19.6mmol) in pyridine (50ml) at rt. The reaction was stirred for 24h then concentrated to dryness in vacuo. The resulting residue was diluted with DCM (100ml), washed with aqueous sodium hydroxide solution (0.5M, 100ml), organic phase separated, dried (MgSO4), filtered and concentrated to dryness in vacuo. Trituration from Et2O and collection by vacuum filtration gave the title compound as a fine off-white solid (5.1g, 14.8mmol, 79%). δH (D-6 DMSO, 300K). m/z (ES+, 70V) 344.1 (MH+)
INTERMEDIATE 2 (DDD73234)
4-Bromo-2,6-dichloro-N-(1 ,3,5-trimethyl-1 H-pyrazol-4-yl)- benzenesulfonamide
Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (5.Og, 15.4mmol) and A- amino-1 ,3,5-trimethyl-1W-pyrazole (1.93g, 15.4mmol) in pyridine (35ml) according to the method of intermediate 1 , to give the title compound as an orange solid (5.64g, 13.7mmol, 89%). δH (D-6 DMSO, 300K) 9.75 (1H, s), 8.00 (2H, s), 3.57 (3H, s), 1.93 (3H, s), 1.72 (3H, s). m/z (ES+, 70V) 413.9 (MH+).
INTERMEDIATE 3 (DDD86208)
4-Bromo-2-chloro-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide
Prepared from 4-bromo-6-chlorobenzene sulfonyl chloride (5.Og, 17.3mmol) and A- amino-1 ,3,5-trimethyl-1H-pyrazole (2.16g, 17.3mmol) in pyridine (35ml) according to the method of intermediate 1 , to give the title compound as an off-white solid (4.1g, 10.8mmol, 62%). δH (D-6 DMSO, 300K) 9.52 (1H1 s), 8.05 (1 H1 d J 1.6Hz), 7.72-7.63 (3H, m), 3.54 (3H1 s), 1.89 (3H, s), 1.69 (3H, s). m/z (ES+, 70V) 379.9 (MH+).
INTERMEDIATE 4 (DDD88004) 4-Bromo-3,6-difluoro-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide Prepared from 2,5-difluoro-4-bromobenzenesulfonyl chloride (2g, 6.9mmol) and 4-amino- 1 ,3,5-trimethyl-1/-/-pyrazole (858mg, 6.9mmol) in pyridine (30ml) according to the method of intermediate 1 , to give the title compound as a pale yellow solid (1.9g, δ.Ommol, 73%). δH (D-6 DMSO1 300K) 9.77 (1 H, s), 8.12 (1 H, dd, J 5.5Hz 9.0Hz), 7.55 (1 H, dd J 6.Hz 7.5Hz), 3.58 (3H, s), 1.92 (3H, s), 1.74 (3H, s). m/z (ES+, 70V) 380.0 (MH+).
INTERMEDIATE 5 (DDD73235)
G-Chloro-pyridine-S-sulfonic acid (1 ,3,5-trimethyl-1 H-pyrazol-4-yl)-amide
Prepared from 6-chloropyridine-3-sulfonyl chloride (4.8g, 22.7mmol) and 4-amino-1 ,3,5- trimethyl-1 H-pyrazole (2.84g, 22.7mmol) in pyridine (35ml) according to the method of intermediate 1 , to give the title compound as a white solid (5.13g, 17.1mmol, 75%). δH (D-6 DMSO, 300K) 9.51 (1 H, s), 8.59 (1 H, d J 2.3Hz)1 8.03 (1 H, dd J 7.6Hz 2.3Hz)1 7.77 (1H, d J 7.6Hz), 3.58 (3H, s), 1.84 (3H, s), 1.63 (3H1 s). m/z (ES+, 70V) 301.1 (MH+).
INTERMEDIATE 6 4-Bromo-N-(3,5-dimethyl-isoxazol-4-yl)-benzenesulfonamide Prepared from 4-bromobenzenesulfonyl chloride (4.56 g, 17.9 mmol) and 4-amino-3,5- dimethylisoxazole (2.02 g, 18.0 mmol) in pyridine (36 ml) according to the method of intermediate 1 , to give the title compound as a white solid (5.15 g, 15.5 mmol, 87%). δH (CDCI3, 300K) 7.69 (2H1 dd, J 6.9Hz 1.7Hz)1 7.65 (2H, dd, J 6.9Hz 1.7Hz), 6.11 (1H, s), 2.12 (3H, S)1 1.91 (3H1 s). m/z (ES+, 70V) 333.0 (MH+).
INTERMEDIATE 7
4-Bromo-2,6-dichloro-N-(3,5-dimethyl-isoxazol-4-yl)-benzenesulfonamide
Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (1.00 g, 3.19mmol) and 4- amino-3,5-dimethylisoxazole (0.346 g, 3.1 mmol) in pyridine (6 ml) according to the method of intermediate 1 , to give the title compound as a tan solid (606mg, 1.51 mmol, 49%). δH (CDCI3, 300K) 7.70 (2 H1 s), 6.66 (1 H, s), 2.23 (3 H, s), 2.05 (3 H, s). m/z (ES+, 70V) 400.9 (MH+).
INTERMEDIATE 8 4-Bromo-N-(2-methyl-pyridin-3-yl)-benzenesulfonamide
Prepared from 4-bromobenzenesulfonyl chloride (4.73g, 18.5mmol) and 2-methyl-3- aminopyridine (2.04g, 18.9mmol) in pyridine (36ml) according to the method of intermediate 1 , to give the title compound as a white solid (3.81 g, 11.6mmol, 63%). δH (CDCI3, 300K) 8.36 (1 H, dd J 4.8Hz 1.5Hz), 7.70 (1 H1 dd J 8.1 Hz 1.5Hz), 7.63 (2H, dd J 6.6Hz 2.3Hz), 7.60 (2H, dd J 6.6Hz 2.3Hz), 7.17 (1 H, dd J 8.1 Hz 4.8Hz), 6.89 (1 H, s), 2.25 (3H1 s). m/z (ES+, 70V) 329.0 (MH+). INTERMEDIATE 9 4-Bromo-2,6-dichloro-N-(2-methyl-pyridin-3-yl)-benzenesulfonamide
Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (1.0Og, 3.1mmol) and 2- methyl-3-aminopyridine (0.33g, 3.1mmol) in pyridine (6ml) according to the method of intermediate 1 , to give the title compound as a yellow solid (0.8Og, 2.0mmol, 65%). δH (CDCI3, 300K) 8.31 (1 H, dd J 4.8Hz 1.4Hz), 7.65 (1 H, d J 1.4Hz), 7.64 (2H, s), 7.10 (2H, m), 2.52 (3H, s). m/z (ES+, 70V) 396.9 (MH+).
INTERMEDIATE 10
4-Bromo-2-fluoro-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide
Prepared from 4-bromo-2-fluorobenzenesulfonyl chloride (0.75g, 2.7mmol) and 4-amino- 1 ,3,5-trimethyl-1H-pyrazole (0.35g, 2.8mmol) in pyridine (4.5ml) according to the method of intermediate 1 , to give the title compound as an orange solid (0.59g, 1.6mmol, 60%). 6H (D-6 DMSO, 300K) 9.60 (1 H, s), 7.90 (1 H, d J 9.4Hz), 7.56 (1 H, d J 8.2Hz), 7.51 (1 H, d J 7.7Hz), 3.56 (3H, s), 1.89 (3H, s), 1.69 (3H, s). m/z (ES+, 70V) 364.0 (MH+).
INTERMEDIATE 11
4-(2-Chloro-pyridin-4-yl)-N-{1#3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide Prototypical procedure for Suzuki coupling of a boronic ester or boronic acid with an aryl halide;
METHOD 1 : A solution of the compound of intermediate 1 (1.5g, 4.36mmol), 2- chloropyridine-4-boronic acid (684mg, 4.35mmol), tribasic potassium phosphate (924mg, 4.35mmol) and Pd(dppf)CI2.DCM (100mg, 0.12mmol) and water (1.5ml) in oxygen-free DMF (8ml) was heated in a microwave at 1300C for 1h. The reaction was concentrated to dryness in vacuo, diluted with DCM (100ml), washed with saturated aqueous sodium hydrogencarbonate solution (2 x 25ml), dried (MgSO4) and concentrated in vacuo to give a residual oil. Chromatography (SiO2, EtOAc) gave the title compound as a fine white solid (1.13g, 2.66mmol, 61 %). δH (D-6 DMSO, 300K) 8.52 (1 H, d J 5.2Hz 7.88 (2H, d J 8.4Hz), 7.74 (2H, d J 8.4Hz), 7.58 (1 H, s), 7.46 (1 H, dd J 1.5Hz 5.2Hz)1 6.36 (1 H, s), 3.71 (3H, s), 2.12 (3H, s), 1.62 (3H, s). m/z (ES+, 70V) 377.1 (MH+).
INTERMEDIATE 12 (DDD86209) 2,6-Dichloro-4-(2-chloro-pyridin-4-yl)-N-(l,3,5-trimethyl-1 H-pyrazol-4-yl)- benzenesulfonamide
Prepared from the sulphonamide of intermediate 2 (250mg, O.δmmol), 2-chloropyridine- 4-boronic acid (108g, 0.67mmol), tribasic potassium phosphate (145mg, 0.68mmol), Pd(dppf)CI2.DCM (20mg, 0.024mmol) and water (0.3ml) in oxygen-free DMF (2.5ml) at 1100C for 1 h according to the method of intermediate 11 , to give the title compound as a white solid (212mg, 0.47mmol, 79%). δH (CDCI3, 300K) 8.38 (1 H, dd J 0.5Hz 5.2Hz), 7.54 (2H, s), 7.37 (1 H, dd J 1.6Hz 5.2Hz), 6.56 (1 H, s), 3.65 (3H, s), 2.09 (3H, s), 1.69 (3H, s). m/z (ES+, 70V) 447.0 (MH+).
INTERMEDIATE 13
4-Bromomethyl-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesυlfonamide 4-Bromomethylbenzene sulfonyl chloride (3.72g, 13.8mmol) was added portionwise to a solution of 4-amino-1 ,3,5-trimethyl-1H-pyrazole (1.73g, 13.8mmol) and pyridine (1.5ml) in DCM (100ml) at rt. Concentration in vacuo gave a solid which was collected by vacuum filtration and washed with water (2x25ml) then Et20 (100ml) to give the title compound as a white solid (2.71 g, 7.59mmol, 55%). δH (D-6 DMSO, 300K) 9.13 (1 H, s), 7.64-7.55 (4H, m), 4.77 (2H, s), 3.55 (3H, s), 1.80 (3H, s), 1.54 (3H, s). m/z (ES+, 70V) 358.1 (MH+).
INTERMEDIATE 14
3'-Formyl-biphenyl-4-sulfonic acid (1 ,3,5-trimethyl-1H-pyrazol-4-yl)-amide
Prepared from the sulphonamide of intermediate 1 (1.54g, 4.48mmol), 3- formylphenylboronic acid (1.4Og, lO.Ommol), tribasic potassium phosphate (1.98g, 9.0mmol), Pd(dppf)CI2.DCM (100mg, 0.12mmol) and water (2ml) in oxygen-free DMF (12ml) at 1300C for 1 h according to the method of intermediate 11 , to give the title compound as a white solid (1.61g, 4.36mmol, 97%). δH (D-6 DMSO, 300K) 10.13 (1 H, s), 9.19 (1 H, s), 8.29 (1 H, t J 1.6Hz), 8.12-8.09 (1H, m), 8.0-7.96 (3H, m), 7.77-7.73 (3H, m), 3.56 (3H, s), 1.84 (3H, s), 1.61 (3H, s). m/z (ES+, 70V) 370.1 (MH+).
INTERMEDIATE 15
3,5-Dichloro-3'-formyl-biphenyl-4-sulfonic acid (1 ,3,5-trimethyM H-pyrazol-4-yl)-amide Prepared from the sulphonamide of intermediate 2 (1.0g, 2.43mmol), 3- formylphenylboronic acid (440mg, 2.91 mmol), tribasic potassium phosphate (620mg, 2.91 mmol), Pd(dppf)CI2.DCM (100mg, 0.12mmol) and water (0.5ml) in oxygen-free DMF (6.0ml) at 1300C for 1h according to the method of intermediate 11, to give the title compound as a white solid (870mg, 2.0mmol, 82%). δH (D-6 DMSO, 300K) 10.12 (1 H, s), 9.68 (1 H, s), 8.42 (1H, s), 8.21 (1 H, d J 7.9Hz), 8.07 (2H, s), 8.01 (1 H, d J 7.5Hz), 7.74 (1 H dd J 7.5Hz 7.9Hz), 3.58 (3H, s), 1.50 (3H, s), 1.75 (3H, s). m/z (ES+, 70V) 439.2 (MH+).
INTERMEDIATE 16
3,5-Dichloro-4'-formyl-bιphenyl-4-sulfonic acid (1 ,3,5-trimethyl-1 H-pyrazol-4-yl)-amide Prepared from the sulphonamide of intermediate 2 (1.Og, 2.43mmol), 4- formylphenylboronic acid (440mg, 2.91 mmol), tribasic potassium phosphate (620mg, 2.91 mmol), Pd(dppf)CI2.DCM (100mg, 0.12mmol) and water (0.5ml) in oxygen-free DMF (6.0ml) at 1300C for 1h according to the method of intermediate 11 , to give the title compound as a white solid (791 mg, 1.83mmol, 75%). δH (D-6 DMSO, 300K) 10.12 (1 H, s), 9.68 (1 H, s), 8.31 (2H, d 7.1 Hz), 8.07 (2H, s), 8.01 (2H, d J 7.1 Hz), 3.58 (3H1 s), 1.50 (3H, s), 1.75 (3H1 s). m/z (ES+, 70V) 439.2 (MH+).
INTERMEDIATE 17
2'-Formyl-biphenyl-4-sulfonic acid (1 ,3,5-trimethyM H-pyrazol-4-yl)-amide
Prepared from the sulphonamide of intermediate 1 (1.0 g, 2.91 mmol), 2-formylphenyl boronic acid (524 mg, 3.49 mmol), tribasic potassium phosphate (740 mg, 3.49 mmol), Pd(dppf)CI2.DCM (119 mg, 0.146 mmol) and water (2.0 ml) in oxygen-free DMF (10.0 ml) at 130 degC for 1 h according to the method of intermediate 10, to give the title compound as a white solid (700mg, 1.90mmol, 65%). δH (CDCI3, 300K) 9.93 (1H, s), 8.05 (1H, d J 7.7Hz), 7.85 (2h, d J 8.5 Hz), 7.68 (1 H, dt J 1.5Hz 7.6 Hz), 7.58 (1 H, t J 1.5 Hz), 7.50 (1 H1 d J 8.5 Hz), 7.39 (1 H, d J 7.7 Hz), 3.69 (3H, s), 2.12 (3H, s), 1.66 (3H, s). m/z (ES+, 70V) 370.1 (M+H+)
INTERMEDIATE 18 (DDD87766)
4-Bromo-N-methyl-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide Prototypical procedure for N-alkylation of a sulphonamide with an alky/ halide; Sodium hydride (88mg, 95% w/w, 3.48mmol) was added portionwise to a solution of Intermediate 1 (1.0g, 2.91 mmol) in DMF (10ml) at 00C. When effervescence had ceased, methyl iodide (217μl, 3.48mmol) was added dropwise and the reaction was allowed to warm to rt over 4h. The reaction was concentrated to dryness in vacuo, diluted by addition of DCM (30ml), washed with water (2 x 15ml), dried (MgSO4) and concentrated in vacuo. The residue was triturated from Et2O and collected by vacuum filtration to give the title compound as a fine off-white solid (557mg, 1.56, 54%). δH (D-6 DMSO, 300K) 9.67 (1 H, s), 8.78 (1 H, d J 5.7Hz), 8.51 (1 H, d J 8.6Hz), 8.09 (1 H, d J 5.8Hz), 7.86 (1 H, d J 5.6Hz), 7.50 (1H, d J 5.7Hz), 7.21 (2H, d J 8.4Hz), 4.17 (2H, d J 8.4Hz), 4.34 (1 H, s), 4.18-4.14 (1 H, m), 3.21 (1 H, dd J 4.9Hz 13.9Hz) 2.98 (1 H, dd J 9.3Hz 13.9Hz), 1.06 (3H, s), 0.99 (3H, s). m/z (ES+, 70V) 404.1 (MH+).
INTERMEDIATE 19 (DDD73490)
4-Bromo-2,6-dichloro-N-methyl-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide Was prepared from the sulphonamide of intermediate 2 (5.Og, 12.2mmol), sodium hydride (95%w/w, 380mg, 15.2mmol) according to the method of intermediate 18 to give the title compound as a brown solid (4.56g, 10.7mmol, 88%). δH (CDCI3, 300K) 7.60 (2H, s), 3.71 (3H, s), 3.40 (3H, s), 2.12 (3H1 s), 1.84 (3H, s). m/z (ES+, 70V) 427.9 (MH+)
INTERMEDIATE 20
4-Bromo-2-methyl-N-( 1 ,3,5-trimethyl-1 H-pyrazol-4-yl)-benzenesulfonamide Prepared from 4-bromo-2-methylbenzenesulfonyl chloride (0.736g, 2.7mmol) and A- amino-1 ,3,5-trimethyl-1/-/-pyrazole (0.35g, 2.8mmol) in pyridine (4.5ml) according to the method of intermediate 1 , to give the title compound as an orange solid (906m, 2.52mmol, 93%). δH (D-6 DMSO, 300K) 9.24 (1 H, s), 7.70 (1 H, d, J 1.5Hz), 7.54 (1 H, dd, J 8.5Hz 1.5Hz), 7.48 (1 H, d 8.5Hz), 3.55 (3H, s), 2.57 (3H, s), 1.82 (3H, s), 1.59 (3H, s). m/z (ES+, 70V) 360.0 (MH+).
INTERMEDIATE 21 (DDD85593)
4-Bromo-2,6-dichloro-IM-(3-hydroxy-propyl)-N-(1 ,3,5-trimethyl-1 H-pyrazol-4-yl)- benzenesulfonamide Prepared from the sulphonamide of intermediate 2 (230mg, 0.56mmol), 3-bromopropanol (500mg, 3.6mmol) and caesium carbonate (325mg, LOmmol) in DMF (1.5ml) according to the method of intermediate 18, to give the title compound as a tan solid (211mg, 0.45mmol, 80%). δH (CDCI3, 300K) 7.58 (2H, s), 4.17-4.11 (2H, m), 3.86-3.75 (2H, m),
3.68 (3H, s), 2.09 (3H, s), 1.79 (3H, s), 1.76-1.69 (2H, m). m/z (ES+, 70V) 472.1 (MH+).
INTERMEDIATE 22
3'-Formyl-biphenyl-4-sulf onic acid methyl-( 1 ,3,5-trimethyl-1 H-pyrazol-4-yl)-amide Prepared from Intermediate 18 (285mg, O.δmmol), 3-formylphenylboronic acid (143mg, LOmmol), tribasic potassium phosphate (169mg, O.δmmol), Pd(dppf)CI2.DCM (33mg, 0.04mmol) and water (0.5ml) in oxygen-free DMF (2ml) at 13O0C for 1 h, according to the method of intermediate 11 , to give the title compound as a white solid (170mg, 0.4mmol, 56%). δH (CDCI3, 300K) 10.12 (1 H, s), 8.13 (1 H, s), 7.94 (1H, d J 7.2Hz), 7.88 (1H, d J 6.6Hz), 7.83 (2H, d J 7.7Hz), 7.76 (2H, d J 6.7Hz), 7.65-7.70 (1H, m), 3.70 (3H, s), 3.22 (3H, s), 2.13 (3H, s), 1.59 (3H, s). m/z (ES+, 70V) 384.0 (MH+).
INTERMEDIATE 23A (DDD88198)
ΦBromo-Z.β-dichloro-N-O-isobutyl-i .δ-dimethyl-IH-pyrazol^-yD-benzenesulfonamide
Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (0.68g, 2.1 mmol) and A- amino-1 ,5-dimethyl-3-isobutyl-1W-pyrazole (0.35g, 2.1mmol) in pyridine (5ml) according to the method of intermediate 1 , to give the title compound as a white solid (120mg, 0.26mmol, 12%). δH (D-6 DMSO, 300K) 7.65 (2H, s), 6.54 (1 H, s), 3.70 (3H, s), 2.17 (3H1 S)1 1.96 (2H, d J 7.9Hz), 1.74 (1H, m), 0.78 (6H, d J 6.6Hz). m/z (ES+, 70V) 456.0 (MH+).
INTERMEDIATE 23B (DDD88197) ΦBromo-Z.β-dichloro-N-tδ-isobutyl-I.S-dimethyl-IH-pyrazol-ΦylJ-benzenesulfonamide Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (0.35g, Hmmol) and A- amino-1,3-dimethyl-5-isobutyl-1/-/-pyrazole (0.18g, 1.1mmol) in pyridine (4ml) according to the method of intermediate 1 , to give the title compound as an orange solid (118mg, 0.26mmol, 24%). δH (D-6 DMSO, 300K) 7.67 (2H, s), 6.69 (1H, s), 3.71 (3H, s), 2.45 (2H, d J 7.8Hz), 1.90 (1H, m), 1.84 (3H, s), 0.91 (6H, d J 6.8Hz). m/z (ES+, 70V) 456.0 (MH+).
INTERMEDIATE 24
5"-Formyl-3'-propoxy-biphenyl-4-sulfonic acid (1 ,3,5-trimethyM H-pyrazol-4-yl)-amide Prepared from the sulphonamide of intermediate 1 (1.0g, 2.91 mmol), 3-formyl-5 propoxyphenyl boronic acid (726mg, 3.49mmol), tribasic potassium phosphate (740mg, 3.49mmol), Pd(dppf)CI2.DCM (119mg, 0.146mmol) and water (2.0ml) in oxygen-free DMF (10.0ml) at 1300C for 1h according to the method of intermediate 10, to give the title compound as a colourless solid (424mg, 0.99mmol, 34%). δH (CDCI3, 300K) 10.04 (1H, s), 7.82 (2H, d J 8.5 Hz), 7.67 (2H, d J 8.5 Hz), 7.67 (1 H, t J 1.4 Hz), 7.43 (1 H, s br), 7.39 (1H, t J 2.4Hz), 5.81 (1 H, s), 4.05 (2H, t J 6.6Hz)1 3.69 (3H1 s), 2.10 (3H, s), 1.87 (2H, h), 1.61 (3H, s), 1.08 (3H, t J 7.5Hz). m/z (ES+, 70V) 428.1 (M+H+).
INTERMEDIATE 25 5'-Formyl-3'-isopropoxy-biphenyl-4-sulfonic acid (1 ,3,5-trimethyl-1 H-pyrazol-4-yl)-amide
Prepared from the sulphonamide of intermediate 1 (1.Og, 2.91 mmol), 3-formyl-5 isopropoxyphenyl boronic acid (726mg, 3.49mmol), tribasic potassium phosphate (740mg, 3.49mmol), Pd(dppf)CI2.DCM (119mg, 0.146mmol) and water (2.0ml) in oxygen- free DMF (10.0 ml) at 1300C for 1 h according to the method of intermediate 10, to give the title compound as a white solid (469 mg, 1.10 mmol, 38 %). δH (CDCI3, 300K) 10.04 (1 H, s), 7.82 (2H, d J 8.4 Hz), 7.71 (2H, d J 8.3 Hz), 7.65 (1 H, s br), 7.41 (1 H, s br), 7.37 (1 H, t J 2.1 Hz), 5.88 (1 H, s), 4.71 (1 H, d J 6.1 Hz), 3.69 (3H, s), 2.10 (3H, s), 1.61 (3H, s), 1.40 (6H, d J 6.1 Hz). m/z (ES+, 70V) 428.2 (M+H+).
INTERMEDIATE 26
4-Bromo-N-(1 ,5-dimethyl-1 H-pyrazol-4-yl)-benzenesulfonamide
Prepared from 4-bromobenzenesulfonyl chloride (0.396g, 1.55mmol) and 4-amino-1 ,5- dimethyl-1 /-/-pyrazole (0.172g, 1.55mmol) in pyridine (3ml) according to the method of intermediate 1 , to give the title compound as a yellow solid (0.362g, 1.10mmol, 71%). δH (D-6 DMSO, 300K) 9.43 (1 H, s), 7.80 (2H, d J 8.7Hz), 7.58 (2H, d J 8.7Hz), 3.63 (3H, s), 1.89 (3 H, s). m/z (ES+, 70V) 332.0 (MH+).
INTERMEDIATE 27 4-Bromo-2,6-dichloro-N-(1 ,5-dimethyl-i H-pyrazol-4-yl)-benzenesulfonamide
Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (500mg, 1.54mmol) and 4- amino-1 ,5-dimethyl-1H-pyrazole (172mg, 1.55mmol) in pyridine (3ml) according to the method of intermediate 1 , to give the title compound as a cream solid (392mg, 0.99mmol, 64%). δH (D-6 DMSO, 300K) 9.91 (1 H, s), 7.97 (2H, s), 3.64 (3H, s), 2.04 (3 H, s). m/z (ES+, 70V) 399.9 (MH+).
INTERMEDIATE 28
4-Bromo-IM-(1 ,3-dimethyl-1 H-pyrazol-4-yl)-benzenesulfonamide
Prepared from 4-bromobenzenesulfonyl chloride (396mg, 1.55mmol) and 4-amino-1 ,3- dimethyl-1 H-pyrazole (228mg, 1.55mmol) in pyridine (3ml) according to the method of intermediate 1 , to give the title compound as a white solid (469mg, 1.42mmol, 92%). δH (D-6 DMSO, 300K) 9.44 (1 H, s), 7.79 (2H, d J 8.7Hz)1 7.57 (2H, d J 8.7Hz), 7.39 (1 H, s), 3.65 (3H, s), 1.70 (3H1 s). m/z (ES+, 70V) 332.0 (MH+).
INTERMEDIATE 29 4-Bromo-2,6-dichIoro-N-( 1 ,3-dimethyl-1 H-pyrazol-4-yl)-benzenesulf onamide
Prepared from 4-bromo-2,6-dichIorobenzenesulfonyl chloride (500mg, 1.54mmol) and A- amino-1 ,3-dimethyl-1H-pyrazole (228mg, 1.55mmol) in pyridine (3ml) according to the method of intermediate 1 , to give the title compound as a pale pink solid (501 mg, 1.26mmol, 82%). δH (CDCI3, 300K) 7.65 (2H, s), 7.31 (1H, s), 6.77 (1H, s), 3.78 (3H, s),
2.04 (3H, s). m/z (ES+, 70V) 399.9 (MH+).
INTERMEDIATE 30
4-Bromo-N-( 1 -methyl-1 H-pyrazol-4-yl)-benzenesulfonamide Prepared from 4-bromobenzenesulfonyl chloride (m396g, 1.55mmol) and 4-amino-1- methyl-1/-/-pyrazole (206mg, 1.54mmol) in pyridine (3ml) according to the method of intermediate 1 , to give the title compound as a white solid (424mg, 1.34mmol, 87%). δH (D-6 DMSO, 300K) 9.80 (1 H1 s), 7.79 (2H, d J 8.7Hz), 7.61 (2H, d J 8.7Hz), 7.48 (1H, s),
7.05 (1 H, s), 3.71 (3H, s). m/z (ES+, 70V) 318.0 (MH+).
INTERMEDIATE 31
4-Bromo-2,6-dichloro-N-(1 -methyl-1 H-pyrazol-4-yl)-benzenesulfonamide Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (500mg, 1 .54mmol) and 4-amino-1 -methyl-1 H-pyrazole (206mg, 1 .54mmol) in pyridine (3ml) according to the method of intermediate 1 , to give the title compound as a white solid (496mg, 1 .29mmol, 84%). δH (D-6 DMSO, 300K) 7.64 (2H, s), 7.45 (1 H, s), 7.18 (1 H, s), 7.01 (1 H, s), 3.85 (3H, s). m/z (ES+, 70V) 385.9 (MH+).
INTERMEDIATE 32 4-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-N-(1 ,3,5-trimethyl-1 H-pyrazol-4-yl)- benzenesulfonamide Prototypical procedure for conversion of an aryl halide to an aryl boronic ester;
The sulphonamide of intermediate 1 (2.22g, 7.5mmol), ό/s-pinacolatodiboron (2.27g, 8.97mmol), potassium acetate (880mg, 15.0mmol) and Pd(dppf)CI2.DCM (110mg) in oxygen-free dioxane (10ml) was heated to 1200C for 1h in a microwave. Concentration in vacuo, dilution with DCM (100ml), washing with water (2x20ml), drying (MgSO4) and concentration in vacuo gave a residue which was triturated with Et2O and collected by vacuum filtration to give the title compound as a pale red solid (1.97g, 5.04mmol, 67%). δH (D-6 DMSO, 300K) 9.18 (1H, s), 7.86 (2H, d J 7.7Hz), 7.68 (2H, d J 7.7Hz)1 3.59 (3H, s), 1.82 (3H, s), 1.68 (3H, s), 1.36 (12H, s). m/z (ES+, 70V) 392.1 (MH+). INTERMEDIATE 33
IM-(2-Methyl-pyridin-3-yl)-4-(4,4,5,5-tetramethyl-t1,3,2]dioxaborolan-2-yl)- benzenesulfonamide
Prepared from the sulphonamide of intermediate 1 (720mg, 2.91 mmol), bis- pinacolatodiboron (880mg, 3.49mmol), potassium acetate (342mg) and Pd(dppf)CI2.DCM
(50mg) in oxygen-free dioxane (4ml) at 12O0C for 1 h according to the method of intermediate 32, to give the title compound as a tan coloured solid (497mg, 1.33mmol,
46%). δH (D-6 DMSO, 300K) 10.03 (1H, s), 8.30 (1H, d J 4.4Hz), 7.86 (2H, d J 8.0Hz),
7.71 (2H, d J 8.0Hz), 7.40 (1H, d J 8.0Hz), 7.20 (1 H, dd J 4.4Hz 8.0Hz), 2.18 (3H, s), 1.35 (12H1 S).
INTERMEDIATE 34
N-(3,5-Dimethyl-isoxazol-4-yl)-4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)- benzenesulfonamide Prepared from the sulphonamide of intermediate 6 (1.01g, 3.06mmol) and bis- pinacolatodiboron (851 mg, 3.35mmol), potassium acetate (881 mg) and Pd(dppf)CI2.DCM (72mg) in oxygen-free dioxane (15ml) at 1200C for 2h according to the method of intermediate 32, to give the title compound as a tan coloured solid (661 mg, 1.75mmol, 57%). δH (CDCI3, 300K) 7.93 (2H, d J 8.3Hz), 7.75 (2H, d J 8.3Hz), 5.86 (1H, s), 2.06 (3H, s), 1.86 (3H, s), 1.38 (12H, s). m/z (ES+, 70V) 379.1 (MH+).
INTERMEDIATE 35
2,6-Dichloro-4-(4,4,5,5-tetramethyl-I1,3,2]dioxaborolan-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-
4-yl)-benzenesulfonamide Prepared from the sulphonamide of intermediate 2 (1.0g, 2.42mmol) and bis- pinacolatodiboron (700mg, 2.76mmol), potassium acetate (750mg) and Pd(dppf)CI2.DCM (60mg) in oxygen-free dioxane (12ml) at 120°C for 2h according to the method of intermediate 32, to give the title compound as an orange-brown solid (1.0g, 2.17mmol, 90%). δH (CDCI3, 300K) 7.83 (2H, s), 6.70 (1H, s), 3.70 (3H, s), 2.14 (3H, s), 1.79 (3H, s), 1.35 (12H, s). m/z (ES+, 70V) 378.0 ([M minus pinacol]H+).
INTERMEDIATE 36 4-[3-(Tetrahydro-pyran-2-yloxy)-prop-1 -ynyl]-IM-(1 ,3,5-trimethyl-1 H-pyrazol-4-yl)- benzenesulfonamide Prototypical procedure for Sonogashira coupling of an an/I halide to an afkyne;
The sulphonamide of intermediate 1 (1.95g, 6.76mmol), tetrahydro-2-(2-propynyloxy)- 2W-pyran (3.5ml, 25.0mmol), CuI (25mg, 0.13mmol) and Pd(PPh3)4 (100mg, 0.08mmol), in DMF (15ml) and NEt3 (10ml) under argon, was heated at 1100C for 1h. The reaction was concentrated in vacuo, diluted with DCM (100ml), washed with brine (2 x 25ml), dried (MgSO4) and concentrated in vacuo to give a crude oil. Chromatography (SiO2,
EtOAc) gave the title compound as a white solid (1.95g, 4.83mmol, 71 %). (D-6 DMSO, 300K) 9.71 (1H, s), 8.15 (2H, d J 8.3Hz), 7.91 (2H, d J 8.3Hz), 4.88 (1H, s), 4.58 (1H, d
J 16.5Hz), 4.49 (1 H, d J 16.5Hz), 3.85-3.75 (1H, m), 3.61 (3H, s), 3.57-3.51 (1H, m), 1.95
(3H, s), 1.78-1.67 (2H, m), 1.75 (3H, s), 1.61-1.45 (4H, m br).
INTERMEDIATE 37 4-(3-Hydroxy-propyl)-N-(1 ,3,5-trimethyl-1 H-pyrazol-4-yl)-benzenesulfonamide
The sulphonamide of intermediate 36 (2.Og, 4.96mmol) and palladium on charcoal (500mg, 10% w/w) in methanol (40ml) under hydrogen was stirred at rt for 24h. The reaction was filtered through celite and the resulting clear solution was treated with 2M HCI in THF (5ml) and stirred for a further 3h. Concentration in vacuo and purification by chromatography (SiO2, EtOAc: MeOH 5:1) gave the title compound as a white powder (1.29g, 3.99mmol, 87%). δH (D-6 DMSO1 300K) 8.99 (1H, s), 7.52 (2H, d J 8.3Hz), 7.38 (2H, d J 8.3Hz), 4.55 (1H, s br), 3.55 (3H, s), 3.39 (2H, t J 6.4Hz), 2.69 (2H, m), 1.80 (3H, s), 1.72 (2H, p J 6.4Hz), 1.53 (3H, s). m/z (ES+, 70V) 324.1 (MH+).
INTERMEDIATE 38
2,6-Dichloro-4-[3-(tetrahydro-pyran-2-yloxy)-prop-1 -ynyl]-N-(1 ,3,5-trimethyM H-pyrazol-4- yl)-benzenesulfonamide
Prepared from the sulphonamide of intermediate 2 (3.4g, 8.23mmol), tetrahydro-2- (2-propynyloxy)-2#-pyran (3.5ml, 25.0mmol), CuI (50mg, 0.26mmol) and Pd(PPhS)4 (250mg, 0.2mmol), in DMF (25ml) and NEts (10ml) according to the method of intermediate 35, to give the title compound as a white solid (2.81 g, 5.97mmol, 73%). δH (D-6 DMSO, 300K) 9.71 (1 H, s), 7.79 (2H, s), 4.88 (1 H, s), 4.58 (1 H, d J 16.5Hz), 4.49 (1 H, d J 16.5Hz), 3.85-3.75 (1 H, m), 3.61 (3H, s), 3.57-3.51 (1 H, m), 1 .95 (3H, s), 1 .78-1 .67 (2H, m), 1 .75 (3H, s), 1 .61 -1 .45 (4H, m br). INTERMEDIATE 39 4-Piperidin-3-yl-piperazine-1-carboxylic acid tert-butyl ester
1-Benzyl-3-piperidone hydrochloride (700mg, 2.7mmol), triethylamine (270mg, 2.7mmol) and 1-(fe/t-butoxycarbonyl)-piperizine (500mg, 2.7mmol) in DCM, was stirred at rt for 1h, then heated to 500C for 40min. Sodium triacetoxyborahydride (1.12g, 5.3mmol) was added and the reaction mixture allowed to cool, with stirring, over 12h then concentrated to dryness in vacuo. The residue was partioned between DCM / water, the organics dried (MgSO4) and concentrated to dryness in vacuo. The resulting residue in EtOH (10ml) was hydrogenated with 10% w/w palladium on carbon (200mg) under hydrogen at rt for 18h. The reaction was filtered through celite and concentrated to dryness in vacuo to give 3-piperazine-1-yl-piperidine as a pale yellow gum (700mg, 2.6mmol, 97%). δH (CDCI3, 300K) 3.43-3.37 (4H, m br), 3.21 (1 H1 d br, J 11.6Hz), 3.01 (1 H, d br, J 12.2Hz), 2.59-2.47 (6H, m br), 2.45-2.38 (1H, m), 1.99-1.92 (1 H, m br), 1.82 -1.75 (1H, m), 1.58- 1.48 (1H, m), 1.45 (9H, s), 1.42-1.33 (1H, m). m/z (ES+, 70V) 270.3 (MH+).
INTERMEDIATE 40 (DDD100805)
4-bromo-2,6-dichloro-N-(difluoromethyl)-N-(1,3,5-trimethyl-1H-pyrazol-4- yl)benzenesulfonamide
A well-stirred slurry containing the compound of intermediate 2 (3.Og, 7.2mmol), potassium carbonate (3.Og, 21mmol) and sodium chlorodifluoroacetate (3.3g, 21mmol) in acetonitrile (100ml) was heated to 6O0C for 48h. The resulting slurry was then concentrated in vacuo, diluted with DCM (100ml) and water (100ml), the organic phase separated, dried (MgSO4) and concentrated in vacuo. Trituration of the residue with diethyl ether gave a precipitate which was collected by vacuum filtration and dried to give the title compound as a fine white powder (2.05g, 4.43mmol, 62%). δH (CDCI3, 300K) 7.61 (2H, s), 7.34 (1H, dd J 59.4Hz 61.2Hz), 3.67 (3H, s), 2.01 (3H1 S)1 1.71 (3H, s). m/z (ES+, 70V) 464.1 (MH+).
INTERMEDIATE 41 4-Bromo-N-(3-isobutyl-1 ,5-dimethyl-1 H-pyrazol-4-yl)-benzenesulf onamide
Prepared from 4-bromobenzenesulfonyl chloride (8.41 g, 32.9mmol) and the amine of intermediate 46 (5.23g, 31.3mmol) in pyridine (80ml) according to the method of intermediate 1 , to give the title compound as a pale yellow solid (9.57g, 24.8mmol, 79%). δH (CDCI3, 300K) 7.61 (4H, m), 5.74 (1H, bs), 3.69 (3H, s), 2.07 (3H1 s), 1.78 (2H, d J 7.0Hz), 1.69 (1 H, m), 0.75 (6H, d J 6.5Hz). m/z (ES+, 70V) 386.1 (MH+). INTERMEDIATE 42
4-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-N-(3-isobutyl-1 ,5-dimethyl-1 H- pγrazol-4~yl)~benzenesulfonamide
Prepared from the sulphonamide of intermediate 41 (1.0Og, 2.59mmol) and bis- pinacolatodiboron (780mg, 3.07mmol), potassium acetate (5601 mg, 5.70mmol) and
Pd(dppf)CI2.DCM (80mg) in oxygen-free dioxane (8ml) at 12O0C for 40min according to the method of intermediate 32, to give the title compound as a grey coloured solid
(919mg, 2.12mmol, 82%). δH (D-6 DMSO, 300K) 323K, 50oC 8.97 (1 H, s), 7.82 (2H, d, J
8.2Hz), 7.67 (2H, d J 8.2Hz), 3.56 (3H, s), 1.90 (2H, d J 7.1 Hz), 1.75 (3H, s), 1.72 (1 H, m), 1.32 (12H, s), 0.72 (6H, d J 6.6Hz). m/z (ES+, 70V) 434.2 (MH+).
INTERMEDIATE 43
1 ,5-Dimethyl-3-(2-methylprop-1 -enyl)-1 H-pyrazole
A suspension of isopropyltriphenylphosphonium iodide (5.23g, 12.1mmol) in THF (35 ml) at -20 0C was treated dropwise with a 1.6 M solution of butyllithium in hexanes (7.5 ml,
12mmol). The mixture was stirred at -20 0C for 45 minutes before a solution of 1 ,5- dimethyl-1 H-pyrazole-3-carboxaldehyde (1.2Og, 9.68mmol) in THF (50ml) was added.
The thick suspension was allowed to warm to room temperature and stirred for 24 hours.
The reaction mixture was treated with saturated aqueous ammonium chloride (150ml) and the phases separated. The aqueous phase was back-extracted with ethyl acetate (3 x 50 ml) and the combined organic phases were dried (Na2SO4) and concentrated. The residue was extracted with petroleum ether (2 x 100ml) and the combined extracts were concentrated to afford a yellow oil which was purified by chromatography (SiO2, 0-100%
EtOAc-petroleum ether) to give the title compound as a colourless solid (1.56g, 9.68mmol). δH (CDCI3, 300K) 6.15 (1H, m), 6.01 (1H, s), 3.75 (3H, s), 2.26 (3H, s), 1.96
(3H, d J 0.8Hz), 1.89 (3H, d J 1.2Hz). m/z (ES+, 70V) 151.1 (MH+).
INTERMEDIATE 44
3-lsobutyl-1 ,5-dimethyM H-pyrazole A solution of the compound of intermediate 43 (1.56g, 9.68 mmol) in methanol (50 ml) was purged with argon and treated with 10% palladium on carbon (0.291g). The reaction vessel was purged with hydrogen and stirred at room temperature overnight. The reaction vessel was purged with argon and further 10% palladium on carbon (0.498g) was added. The mixture stirred under hydrogen for a further 24 hours, then filtered through celite and concentrated. The residue was resuspended in petroleum ether 40-60 (100ml), filtered and concentrated. The resulting residue was again suspended in petroleum ether (50ml), re-filtered and concentrated to give the title compound (1.064g, 6.99mmol, 72%) as a pale yellow oil. δH (CDCI3, 300K) 5.78 (3H, s), 3.71 (3H, s), 2.40 (2H, d J 7.1Hz), 2.22 (3H, s), 1.87 (1 H, m), 0.92 (6H, d J 6.6Hz). m/z (ES+, 70V) 153.1 (MH+).
INTERMEDIATE 45
3-lsobutyl-1 ,5-dimethyl-4-nitro-1 H-pyrazole
The compound of intermediate 44 (1.049g, 6.89mmol) at O0C was treated with concentrated sulphuric acid (3.5 ml, 66 mmol). Nitric acid (90%, 2.8ml, 67mmol) was added dropwise at the same temperature. The cooling bath was removed and the mixture heated at 100 0C for 2h. The mixture was then cooled, poured onto ice (150 ml), basified with aqueous sodium hydroxide (2M, 100ml) and extracted with diethyl ether (3 x 100ml). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to give the title compound as a yellow oil (1.082g, 5.49mmol, 80%). δH (CDCI3, 300K) 3.79 (3H, s), 2.77 (2H, d J 7.1Hz), 2.60 (3H, s), 2.04 (1H, m), 0.94 (6H, d J 6.7Hz). m/z (ES+, 70V) 198.1 (MH+).
INTERMEDIATE 46
3-lsobutyl-1 ,5-dimethyl-1 H-pyrazol-4-amine The compound of intermediate 45 (1.072g, 5.44mmol) in methanol (25ml) under argon was treated with 10% palladium on carbon (0.174 g). The reaction vessel was purged with hydrogen and stirred at room temperature for 23 hours. The reaction mixture was filtered through a plug of celite and concentrated. The residue was dissolved in dichloromethane, re-filtered and concentrated to give the title compound as a red oil (0.886g, 5.30mmol, 97%). δH (CDCI3, 300K) 3.67 (3H, s), 2.48 (2H, br.s), 2.39 (2H, d J 7.2Hz), 2.13 (3H, s), 1.92 (1H, m), 0.94 (6H, d J 6.7Hz). m/z (ES+, 70V) 168.2 (MH+).
INTERMEDIATE 47
4-bromo-2,6-dichloro-N-(2,2,2-trifluoroethyl)-N-(1,3,5-trimethyl-1H-pyrazol-4- yl)benzenesulfonamide
The compound of intermediate 2 (200mg, 0.48mmol) and K2CO3 (127mg, 0.96mmol) in acetonitrile (2.OmL) was treated dropwise with 2,2,2-trifluoroethyl methanesulphonate (0.139mL, 223mg, 0.139mmol) and the mixture heated in a microwave at 1000C for 30min. The mixture was then diluted with ethyl acetate (30.OmL) and the organic layer washed with water (2 x 1OmL), brine (1OmL), dried over MgSO4 and concentrated in vacuo. The crude material was purified by column chromatography (SiO2, 6:4 Hexanes: EtOAc) to give the title compound as a colourless solid (217mg, 0.44mmol, 91%). δH (CDCI3, 300K) 7.58 (2H, s), 4.82-4.68 (1 H, m), 3.97-3.68 (1 H, m), 3.68 (3H, s), 2.17 (3H, s), 1.68 (3H, s). m/z (ES+, 70V) 496.2 (M+H+).
EXAMPLE DDD73498
6-(8-Amino-3,4-dihydro-1 H-isoquinolin-2-yl)-pyridine-3-sulfonic acid (1 ,3,5- trimethyl-1 H-pyrazoI-4-yl)-amide
Prepared from the sulphonamide of intermediate 5 (1.33gmg, 4.43mmol) and 5-amino- 1 ,2,3,4-tetrahydroisoquinoline (1.31g, 8.8mmol) in ethanol (0.75ml), according to the method of example DDD86213, to give the title compound as a white powder (1.21g, 2.94mmol, 66%). δH (CDCI3, 300K) 8.41 (1 H, d J 2.5Hz), 7.64 (1 H, dd J 2.5Hz 9.1 Hz), 7.36 (1 H1 s), 7.03 (1 H, t J 7.8Hz), 6.69 (2H, t J 7.8Hz), 6.58 (1 H, d J 9.1Hz), 4.70 (2H, s), 3.95 (2H, t J 6.0Hz), 3.62 (3H, s), 2.72 (2H, t J 6.0Hz), 2.01 (3H, s), 1.74 (3H, s). m/z (ES+, 70V) 413.2 (MH+).
EXAMPLE DDD85602
6-[2-(4-Methyl-piperazin-1-yl)-ethylamino]-pyridine-3-sulfonic acid (1,3,5-trimethyl- 1 H-pyrazol-4-yl)-amide Prepared from the sulphonamide of intermediate 5 (225mg, 0.75mmol) and 4-(2- aminoethyl)-methylpiperazine (0.5ml) in ethanol (0.75ml), according to the method of example DDD86213, to give the title compound as a white powder (198mg, 0.49mmol, 65%). δH (D-6 DMSO, 300K) 8.77 (1 H, s), 8.07 (1 H, d J 2.4Hz), 7.45 (1H, dd J 2.2Hz 8.9Hz), 7.28 (1 H, s br), 6.54 (1 H, d J 8.9Hz), 3.57 (3H1 s), 3.44-3.39 (2H, m), 2.41 (2H, t J 6.1Hz), 2.41 (4H, s br), 2.36-2.31 (4H and 3H, s br), 2.16 (3H, s), 1.89 (3H1 s), 1.67 (3H, s). m/z (ES+, 70V) 408.2 (MH+).
EXAMPLE DDD85646
2,6-Dichloro-4-(2-piperazin-1 -yl-pyridin-4-yl)-N-(1 ,3,5-trimethyM H-pyrazol-4-yl)- benzenesulfonamide Prepared from the sulphonamide of intermediate 2 (250mg, 0.61 mmol), 2-(1- piperazinyl)pyridine-4-boronic acid pinacol ester (211mg, 0.73mmol), tribasic potassium phosphate (155mg, 0.73mmol), and Pd(dppf)CI2.DCM (30mg, 0.36mmol) in DMF (2.5ml) and water (0.50ml), according to the method of intermediate 11 , to give the title compound as an off-white powder (150mg, 0.30mmol, 50%). δH (D-6 DMSO, 300K) 9.79 (1H1 s), 8.25 (1H, d J 5.9Hz), 8.20 (2H1 S)1 7.61 (1H, s), 7.40 (1H1 d J 5.9Hz), 4.08 (4H1 s br), 3.63 (3H, s), 3.28 (4H1 s br), 2.00 (3H, s), 1.77 (3H1 s). m/z (ES+, 70V) 496.1 (MH+). EXAMPLE DDD86206
2-Chloro-4-(2-piperazin-1 -yl-pyridin-4-yl)-N-( 1 ,3,5-trimethyM H-pyrazol-4-yl)- benzenesuifonamide Prepared from the sulphonamide of intermediate 3 (500mg, 1.3mmol), 2-(1- piperazinyl)pyridine-4-boronic acid pinacol ester (580mg, 2.0mmol), tribasic potassium phosphate (427mg, 2.0mmol), and Pd(dppf)CI2.DCM (50mg, 0.06mmol) in DMF (3.0ml) and water (0.75ml), according to the method of intermediate 11 , to give the title compound as an off-white powder (412mg, 0.89mmol, 68%). δH (D-6 DMSO, 300K) 8.20 (1H, d J 5.2Hz), 8.14 (1H, d J 1.7Hz), 7.84 (1H, dd J 1.75Hz 8.3Hz), 7.79 (1H, d J 8.3Hz), 7.13 (1H, s), 6.99 (1H, dd J 1.15Hz 5.2Hz), 3.55 (3H, s), 3.51 (4H, s br), 2.79 (4H, s br), 1.90 (3H, s), 1.69 (3H, s). m/z (ES+, 70V) 461.2 (MH+).
EXAMPLE DDD86211 2,6-Dichloro-4-[2-(4-methyl-piperazin-1 -yl)-pyridin-4-yl]-N-( 1 ,3,5-trimethyM H-pyrazol-4-yl)- benzenesυlfonamide
Prepared by heating the chloropyridine of intermediate 12 (90mg, 0.2mmol) with N- methylpiperazine (100μl) in EtOH (1.5ml) at150°C for 1h according to the method of DDD86213 to give the title compound as an off-white powder (45mg, O.Oδmmol, 40%). δH (CDCI3, 300K) 8.54 (1 H, d J 5.1 Hz), 7.57 (1 H, d J 1.8Hz), 7.53 (1 H, d J 0.95Hz), 7.46 (1H, s), 7.42 (1H, dd J 1.6Hz 5.1Hz), 3.69 (3H, s), 3.29 (4H, s br), 2.66 (3H, s), 2.42 (4H, s br), 2.17 (3H, s), 1.80 (3H, s). m/z (ES+, 70V) 509.1 (MH+).
EXAMPLE DDD86212 3'-(4-Methyl-piperazin-1-ylmethyl)-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H- pyrazol-4-yl)-amide
Prototypical procedure for the reductive amination of an aldehyde with an alkylamine; The aldehyde of intermediate 14 (200mg, 0.54mmol), N-methylpiperazine (100mg, LOmmol) and sodium triacetoxyborohydride (400mg, 1.90mmol) in CHCI3 (15ml) was heated at 500C for 24h. Dilution with DCM (25ml), washing with water (2 x 10ml), drying (MgSO4) and concentration in vacuo gave a gum which was subjected to chromatography (SiO∑, 50:10:1 EtOAc: MeOH: saturated aqueous ammonia solution) to give the title compound as a white powder (217mg, 0.48mmol, 89%). δH (D-6 DMSO, 300K) 9.20 (1 H, s), 8.11 (1 H, s br), 7.96 (2H, d J 8.4Hz), 7.83 (1 H, d J 6.95Hz), 7.71 (2H, d J 8.4Hz), 7.67 (1H, s br), 7.59 (1H, t J 7.6Hz), 3.63 (2H, s), 3.57 (3H, s), 3.44 (4H, s br), 2.81 (4H, s br), 1.85 (3H, s), 1.58 (3H, s). m/z (ES+, 70V) 453.1 (MH+).
EXAMPLE DDD86213 4-(2-Piperazin-1 -yl-pyridin-4-yl)-N-(1 ,3,5-tιϊmethyl-1 H-pyrazol-4-yl)- benzenesulfonamide
Prototypical procedure for preparation of a 2-aminopyridine by displacement reaction of a 2-chloropyridine with an alkylamine; METHOD 1: The compound of intermediate 11 (250mg, 0.66mmol) and piperazine (500mg, 5.8mmol) in EtOH (0.75ml) was heated at 1550C for 2h by microwave in a sealed vessel. Dilution with DCM (25ml), washing with aqueous sodium hydrogencarbonate solution (2 x 5ml), drying (MgSO4) and concentration in vacuo gave a residual oil which was subjected to chromatography (SiO2, 50:10:1 EtOAc:MeOH: saturated aqueous ammonia solution) to give the title compound as a white powder (189mg, 0.44mmol, 67%). δH (D-6 DMSO, 300K) 8.24 (1H1 d J 5.2Hz), 8.00 (2H, dd J 1.8Hz 6.7Hz), 7.74 (2H, dd J 1.8Hz 6.7Hz), 7.12 (1 H, s), 7.00 (1 H, dd J 5.2Hz 1.4Hz)1 3.60 (3H1 s), 3.54 (4H, s br), 2.84 (4H, s br), 1.87 (3H, s), 1.68 (3H, s). m/z (ES+, 70V) 426.1 (MH+).
METHOD 2: Alternatively this compound could be prepared by Suzuki reaction of the sulphonamide of intermediate 1 (500mg, 1.68mmol), 2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (581 mg, 2.0mmol), tribasic potassium phosphate (427mg, 2.0mmol), and Pd(dppf)CI2.DCM (50mg, 0.06mmol) in DMF (3.0ml) and water (0.75ml), according to the method of intermediate 11 , to give the title compound as an off-white powder (381 mg, 0.89mmol, 53%).
EXAMPLE DDD86292
2,6-Dichloro-4-[2-(3-dimethylamino-pyrrolidin-1-yl)-pyridin-4-yl]-N-(1,3,5-trimethyl-
1H-pyrazol-4-yl)-benzenesulfonamide Prepared by heating the chloropyridine of intermediate 12 (250mg, 0.58mmol) with 3- dimethylaminopiperidine (200μl) in EtOH (1.5ml) at 1550C for 1h according to the method of DDD86213 to give the title compound as a white powder (150mg, 0.29mmol, 49%). δH (CDCI3, 300K) 8.48 (1H, d J 5.1 Hz), 7.49 (2H, s), 7.39 (1H, d J 4.7Hz), 7.32 (1 H, s), 3.76-3.46 (6H, s br), 3.63 (3H, s), 3.46-3.39 (1 H, m), 2.75 (2H, s br), 2.28 (2H, s br), 2.05 (3H1 s), 1.85 (3H, s), 1.56 (2H, s br). m/z (ES+, 70V) 523.2 (MH+). EXAMPLE DDD86297
2,6-Dichloro-4-[2-(2-methylamino-ethylamino)-pyridin-4-yl]-N-(1,3,5-trimethyl-1 H- pyrazol-4-yl)-benzenesulfonamide
Prepared by heating the chloropyridine of intermediate 12 (250mg, 0.58mmol) with N- methyiethylenediamine (200μl) in EtOH (1.5ml) at 155°C for 1h according to the method of DDD86213 to give the title compound as a white powder (134mg, 0.28mmol, 48%). δH (D-6 DMSO, 300K) 8.53 (1 H, d J 5.2Hz), 7.98 (1 H, d J 0.9Hz), 7.85 (1 H, dd J 1.5Hz
5.2Hz), 7.28 (1 H, s), 7.21 (1 H, d J 1.5Hz), 7.04 (1 H, d J 1.5Hz), 3.60 (3H, s), 3.24-3.20
(2H, m), 2.64-2.58 (2H, m), 2.29 (3H, s), 1.98 (3H, s), 1.82 (3H, s). m/z (ES+, 70V) 483.1 (MH+).
EXAMPLE DDD86302
2,6-Dichloro-4-{2-[2-(pyridin-2-ylamino)-ethylamino]-pyridin-4-yl}-N-(1,3,5-trimethyl-
1 H-pyrazol-4-yl)-benzenesulfonamide Prepared by heating the chloropyridine of intermediate 12 (250mg, 0.58mmol) with N-(2- pyridyl)ethylenediamine (200μl) in EtOH (1.5ml) at 155°C for 1 h according to the method of DDD86213 to give the title compound as a white powder (111 mg, 0.2mmol, 35%). δH (D-6 DMSO, 300K) 9.41 (1 H, s), 8.51 (1 H, d J 5.1Hz), 7.93 (1 H, d J 4.9Hz), 7.91 (1 H, s), 7.79 (1 H, d J 5.2Hz), 7.36 (1 H1 1 J 7.1Hz), 7.27 (1 H1 s), 7.20-7.18 (1 H, m), 7.17 (1 H, s), 6.60 (1 H, s), 6.54-6.44 (2H, m), 3.55 (3H, s), 3.41-3.23 (4H, m), 1.92 (3H, s), 1.79 (3H1 s). m/z (ES+, 70V) 546.1 (MH+).
EXAMPLE DDD86303
2,6-Dichloro-4-{2-[2-(pyridin-2-ylamino)-ethylamino]-pyridin-4-yl}-N-(1,3,5-trimethyl- 1 H-pyrazol-4-yl)-benzenesulfonamide
Prepared by heating the chloropyridine of intermediate 12 (250mg, 0.58mmol) with ethylenediamine (200μl) in EtOH (1.5ml) at 1550C for 1 h according to the method of DDD86213 to give the title compound as a white powder (137mg, 0.29mmol, 50%). δH (D-6 DMSO, 300K) 8.49 (1 H, d J 4.1 Hz), 7.93 (1H, s), 7.80 (1H, d J 4.9Hz), 7.22 (1 H, s br), 7.17 (1 H, s), 7.01 (1H, s), 4.03 (2H, s br), 3.55 (3H, s), 3.16 (2H, s br), 2.63 (2H, t J 7.1 Hz)1 1.94 (3H, s), 1.78 (3H1 s). m/z (ES+, 70V) 469.2 (MH+).
EXAMPLE DDD86308
2,6-Dichloro-4-[2-(3-imidazol-1 -yl-propylamino)-pyridin-4-yl]-N-(1 ,3,5-trimethyM H- pyrazol-4-yl)-benzenesulfonamide Prepared by heating the chloropyridine of intermediate 12 (250mg, 0.58mmol) with N-(3- aminopropyl)imidazole (200μl) in EtOH (1.5ml) at 155°C for 1 h according to the method of DDD86213 to give the title compound as a white powder (130mg, 0.24mmol, 41%). δH (CDCI3, 300K) 8.46 (1 H, dd J 0.5Hz 5.1Hz), 7.52 (1 H1 s), 7.46 (1H, dd J 0.5Hz 1.5Hz), 7.35 (1H, dd J 1.5Hz 5.2Hz), 7.24 (1H, t J 4.9Hz), 7.1Hz (1H, s), 7.00 (1H, d J 1.8Hz), 6.83 (2H, s), 6.58 (1H, d J 1.8Hz), 3.92 (2H, t J 6.1 Hz), 3.60 (3H, s), 3.04 (2H, q J 6.1Hz), 2.13 (3H, s), 2.05 (2H, p J 6.1 Hz), 1.89 (3H, s). m/z (ES+, 70V) 534.1 (MH+).
EXAMPLE DDD86309 2,6-Dichloro-4-[2-(2-dimethylamino-ethylamino)-pyridin-4-yl]-N-(1 ,3,5-trimethyM H- pyrazol-4-yl)-benzenesulfonamide
Prepared by heating the chloropyridine of intermediate 12 (250mg, 0.58mmol) with N1N- dimethylethylenediamine (200μl) in EtOH (1.5ml) at 155°C for 1h according to the method of DDD86213 to give the title compound as a white powder (70mg, 0.14mmol, 24%). δH (CDCI3, 300K) 8.50 (1H1 d J 5.1Hz)1 7.53 (1H1 s), 7.44 (1H1 d J 3.8Hz), 7.39 (1 H1 1 J 4.5Hz)1 7.02 (1 H1 s), 6.98 (1H1 s), 6.76 (1H1 s), 3.68 (3H, s), 3.27 ("h, s br), 2.60 (2H1 s br), 2.31 (6H1 s br), 2.14 (3H1 s), 2.89 (3H1 s). m/z (ES+, 70V) 497.1 (MH+).
EXAMPLE DDD86312 3'-Diethylaminomethyl-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)- amide
Prepared from the aldehyde of intermediate 14 (80mg, 0.23mmol), diethylamine (0.088ml, 50mg, 0.069mmol) and sodium triacetoxyborohydride (146mg, 0.069mmol) in CHCI3 (5.0 ml) at 5O0C for 24h according to the method of example DDD86212 to give the title compound as a white solid (55mg, 0.13mmol, 56%). δH (CDCI3, 300K) 7.78 (2H, d J 8.6 Hz)1 7.71 (2H1 d J 8.5 Hz)1 7.66 (1H1 s br), 7.50 (1 H, d J 6.8Hz), 7.42 (2H, d J 5.8 Hz), 5.84 (1 H1 s), 3.71 (1H1 s br), 3.68 (3H, s), 2.64 (3H1 s br), 2.08 (3H1 s), 1.62 (3H1 s), 1.13 (6H1 s br). m/z (ES+, 70V) 427.2 (MH+).
EXAMPLE DDD86314
3'-Morpholin-4-ylmethyl-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)- amide
Prepared from the aldehyde intermediate 14 (150mg, 0.41 mmol), morpholine (107μl,
107mg, 1.23mmol) and sodium triacetoxyborohydride (261 mg, 1.23mmo!) in CHCI3 (10.0 ml) at 5O0C for 24h according to the method of example DDD86212 to give the title compound as a white solid (90mg, 0.21 mmol, 50%). δH (CDCI3, 300K) 7.79 (2H1 d J 8.3Hz), 7.69 (2H, d J 8.3Hz), 7.57 (1H, s br), 7.50 (1 H, d J 7.5Hz)1 7.43 (1 H, t J 7.5Hz), 7.39 (1H, d J 7.5Hz), 5.74 (1 H, s br), 3.73 (3H, t J 4.6Hz), 3.69 (3H, s), 3.57 (2H, s), 2.49 (3H, s br), 2.11 (3H, s), 1.61 (3H, s), 1.55 (1 H, s br). m/z (ES+, 70V) 441.1 (MH+).
EXAMPLE DDD86315
4-[4'-(1,3,5-Trimethyl-1H-pyrazoI-4-ylsulfamoyl)-biphenyl-3-ylmethyl]-piperazine-1- carboxylic acid tert-butyl ester
Prepared from the aldehyde of intermediate 14 (150mg, 0.41 mmol), N-Boc piperazine (229mg, 1.23mmol) and sodium triacetoxyborohydride (261 mg, 1.23mmol) in CHCI3 (10.0 ml) at 500C for 24 h according to the method of example DDD86212 to give the title compound as a white solid (120mg, 0.14mmol, 54%). δH (CDCI3, 300K) 7.79 (2H, d J 8.4Hz), 7.69 (2H, d J 8.4Hz), 7.56 (1H, s br), 7.50 (1 H, d, J 7.7Hz), 7.43 (1 H, t J 7.6Hz), 7.38 (1H, d, J 7.7Hz), 5.74 (1 H, s), 3.69 (3H, s), 3.58 (2H, s), 3.45 (4H, t J 5.0Hz), 2.43 (4H, t J 4.5Hz), 2.11 (3H, s), 1.54 (3H, s), 1.46 (9H, s). m/z (ES+, 70V) 540.1 (MH+).
EXAMPLE DDD86316
3'-[(2-Dimethylamino-ethylamino)-methy]]-biphenyl-4-sulfonic acid (1 ,3,5-trimethyI- 1 H-pyrazol-4-yl)-amide Prepared from the aldehyde of intermediate 14 (150mg, 0.41 mmol), NN'- dimethylethylenediamine (134μl, 108mg, 1.23mmol) and sodium triacetoxyborohydride (261 mg, 1.23mmol) in CHCI3 (10.0ml) at 50°C for 18h according to the method of example DDD86212 to give the title compound as a white solid (60mg, 0.14mmol, 33%). δH (CDCI3, 300K) 7.78 (2H, d J 8.4 Hz), 7.69 (2H, d J 8.5 Hz), 7.59 (1 H, s br), 7.48 (1 H, d J 7.6 Hz), 7.43 (1 H, t J 7.5 Hz), 7.38 (1 H, d J 7.5 Hz), 5.75 (1 H, s), 3.89 (2H, s), 3.68 (3H, s), 2.74 (2H, t J 5.9 Hz), 2.46 (2H, t J 6.2 Hz), 2.22 (6H, s), 2.08 (3H, s), 1.63 (3H, s). m/z (ES+, 70V) 442.1 (MH+).
EXAMPLE DDD86317
S'-Piperazin-i-ylmethyl-biphenyM-sulfonic acid (1,3,5-trimethyM H-pyrazol-4-yl)- amide
Prepared from the aldehyde of intermediate 14 (150mg, 0.41 mmol), piperazine (106mg, 1.23mmol) and sodium triacetoxyborohydride (261 mg, 1.23mmol) in CHCI3 (10.0ml) at 5O0C for 24h according to the method of example DDD86212 to give the title compound as a white solid (94mg, 0.21 mmol, 52.0%). δH (CDCI3, 300K) 7.79 (2H1 d J 8.4 Hz), 7.69 (2H, d J 8.3 Hz)1 7.56 (1H, s br), 7.49 (1 H1 d J 7.6 Hz), 7.42 (1 H, t J 7.6 Hz), 7.38 (1H, d J 7.5 Hz), 5.87 (1H, s br), 3.68 (3H, s), 3.58 (2H, s), 2.96 (4H, t J 4.8Hz), 2.51 (4H, s br), 2.10 (3H, s), 1.62 (3H, s). m/z (ES+, 70V) 440.1 (MH+).
EXAMPLE DDD86318 3'-Pyrrolidin-1-ylmethyl-biphenyl-4-sulfonic acid (1,3,5-trimethyMH-pyrazol-4-yl)- amide
Prepared from the aldehyde of intermediate 14 (80mg, 0.23mmol), pyrrolidine (57.0μl, 49mg, 0.069mmol) and sodium triacetoxyborohydride (146mg, 0.069mmol) in CHCI3 (5.0 ml) at 500C for 24h according to the method of example DDD86212 to give the title compound as a white solid (85mg, 0.20mmol, 87%). δH (CDCI3, 300K) 7.78 (2H, d J 8.4Hz), 7.71 (2H, d J 8.3Hz), 7.51 (2H, s br), 7.43 (2H, d J 6.6Hz), 5.76 (1H, s), 3.77 (2H, s br), 3.68 (3H, s), 2.64 (4h, s br), 2.08 (3H, s), 1.86 (4H, s br), 1.64 (3H, s). m/z (ES+, 70V) 425.1 (MH+).
EXAMPLE DDD86467
2,6-Dichloro-N-(5-isobutyl-1,3-dimethyl-1H-pyrazol-4-yl)-4-(2-piperazin-1-yl-pyridin- 4-yl)-benzenesulfonamide
Prepared from the sulphonamide of intermediate 23B (115mg, 0.25mmol), 2-(1- piperazinyl)pyridine-4-boronic acid pinacol ester (80mg, 0.28mmol), tribasic potassium phosphate (60mg, 0.28mmoi), and Pd(PPh3)4 (30mg, 0.026mmol) in DMF (1.6ml) and water (0.4ml), according to the method of intermediate 11 , to give the title compound as a yellow solid (50mg, 0.09mmol, 37%). δH (D-6 DMSO, 300K) 8.20, (1H, d, J 5.3Hz), 8.07 (2H, s), 7.16 (1 H, s), 7.03 (1 H, d, J 5.3 Hz), 3.59 (3H, s), 3.52 (4H, m), 2.80 (4H, m), 2.21 (2H, d J 7.5Hz), 1.98 (1H, m), 1.77 (3H, s), 0.75 (6H, d J 6.6Hz). m/z (ES+, 70V) 537.2 (MH+).
EXAMPLE DDD86468
2,6-Dichloro-N-(3,5-dimethyl-isoxazol-4-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)- benzenesulfonamide Prepared from the sulphonamide of intermediate 7 (100mg, 0.25mmol), 2-(1- piperazinyl)pyridine-4-boronic acid pinacol ester (87mg, 0.30mmol), tribasic potassium phosphate (72mg, 0.34mmol), and Pd(PPh3)4 (30mg, 0.026mmol) in DMF (1.6ml) and water (0.4ml), according to the method of intermediate 11 , to give the title compound as a yellow solid (12mg, 0.025mmol, 10%). δH (D-6 DMSO, 300K) 8.20, (1H, d J 5.3Hz), 7.94 (2H1 s), 7.21 (1H, s), 7.08 (1H, d J 5.3 Hz)1 3.65 (4H, m), 2.97 (4H, m), 1.96 (3H, s), 1.91 (3H, s). m/z (ES+, 70V) 482.1 (MH+). EXAMPLE DDD86469
2,6-Dichloro-4-[3-(4-methyl-piperazin-1 -yl)-prop-1 -ynyl]-N-(1 ,3,5-trimethyI-1 H- pyrazol-4-yl)-benzenesuIfonamide Prepared from the sulphonamide of intermediate 2 (355mg, O.δδmmol), 1 -methyl-4-prop- 2-ynyl-piperazine (142mg, 1.03mmol), CuI (8.2mg, 0.043mmol) and Pd(PPh3)4 (50mg, 0.043mmol), in DMF (3.0ml) and NEt3 (2.0ml) according to the method of intermediate 36, to give the title compound as an off-white solid (150mg, 0.32mmol, 37%). δH (CDCI3, 300K) 7.47 (2H, s), 6.58 (1H, s), 3.67 (3H, s), 3.56 (2H, s), 2.67 (4H, s br), 2.51 (4H, s br), 2.32 (3H, s br), 2.13 (3H, s), 1.78 (3H, s). m/z (ES+, 70V) 470.1 (MH+).
EXAMPLE DDD86470
2,6-DichIoro-N-(3,5-dimethyl-isoxazol-4-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)- benzenesulfonamide Prepared from the boronic ester of intermediate 35 (184mg, 0.4mmol), 4-(3- bromophenyl)piperidine hydrochloride (133mg, 0.48mmol), tribasic potassium phosphate (144mg, 0.68mmol), and Pd(PPh3)4 (48mg, 0.042mmol) in DMF (3.2ml) and water (0.8ml), according to the method of intermediate 11 , to give the title compound as a yellow solid (20mg, 0.040mmol, 16%). δH (CDCI3, 300K) 7.63 (2H, s), 7.41 (3H, m), 7.33 (1 H, d J 6.6 Hz), 3.68 (3H, s), 3.23 (2H, d J 12.0 Hz), 2.78 (2H, dt J 12.1 Hz 2.1 Hz), 2.71 (1 H, tt J 12.1 Hz 3.6Hz), 2.18 (3H, s), 1.88 (2H, d J 12.6Hz), 1.73 (3H, s), 1.70 (2H, qd J 12.5Hz 3.8Hz). m/z (ES+, 70V) 493.1 (MH+).
EXAMPLE DDD86471 N-(1 ,3-Dimethyl-1 H-pyrazol-4-yl)-4-(2-piperazin-1 -yl-pyridin-4-yl)- benzenesulfonamide
Prepared from the sulphonamide of intermediate 28 (83mg, 0.25mmol), 2-(1- piperazinyl)pyridine-4-boronic acid pinacol ester (80mg, 0.28mmol), tribasic potassium phosphate (60mg, 0.28mmol), and Pd(PPh3)4 (30mg, 0.026mmol) in DMF (1.6ml) and water (0.6ml), according to the method of intermediate 11 , to give the title compound as a white solid (48mg, 0.12mmol, 47%). δH (D-6 DMSO, 300K) 8.20 (1 H, d J 5.2Hz), 7.95 (2H, d J 8.3Hz), 7.74 (2H, d J 8.3Hz), 7.41 (1 H, s), 7.08 (1 H, s), 6.97 (1H1 d J 5.2Hz), 3.65 (3H, s), 3.50 (4H, m), 2.80 (4H, m), 1.70 (3H, s). m/z (ES+, 70V) 413.2 (MH+).
EXAMPLE DDD86474
N-(1 -Methyl-1 H-pyrazol-4-yl)-4-(2-piperazin-1 -y|-pyridin-4-yl)-benzenesulfonamide Prepared from the sulphonamide of intermediate 30 (79mg, 0.25mmol), 2-(1- piperazinyl)pyridine-4-boronic acid pinacol ester (80mg, 0.28mmol), tribasic potassium phosphate (60mg, 0.28mmol), and Pd(PPh3)4 (30mg, 0.026mmol) in DMF (1.6ml) and water (0.6ml), according to the method of intermediate 11 , to give the title compound as a white solid (46mg, 0.12mmol, 47%). δH (D-6 DMSO, 300K) 8.19 (1 H, d J 5.2Hz), 7.93 (2H, d J 8.4Hz), 7.78 (2H, d J 8.4Hz), 7.49 (1 H, s), 7.06 (2H, s), 6.95 (1 H1 d J 5.2Hz), 3.71 (3H, s), 3.49 (4H, m), 2.79 (4H, m). m/z (ES+, 70V) 399.2 (MH+).
EXAMPLE DDD86475 2,6-Dichloro-N-(1 ,3-dimethyl-1 H-pyrazol-4-yl)-4-(2-piperazin-1 -yl-pyrϊdin-4-yl)- benzenesulfonamide
Prepared from the sulphonamide of intermediate 29 (100mg, 0.25mmol), 2-(1- piperazinyl)pyridine-4-boronic acid pinacol ester (80mg, 0.28mmol), tribasic potassium phosphate (60mg, 0.28mmol), and Pd(PPh3)4 (30mg, 0.026mmol) in DMF (1.6ml) and water (0.6ml), according to the method of intermediate 11 , to give the title compound as a white solid (14mg, 0.03mmol, 12%). δH (D-6 DMSO, 300K) 8.16 (1 H1 d J 5.2Hz), 7.97 (2H, s), 7.41 (1 H, s), 7.12 (1 H, s), 7.00 (1 H, d J 5.2Hz), 3.60 (3H, s), 3.50 (4H, m), 2.77 (4H, m), 1.84 (3H, s). m/z (ES+, 70V) 481.1 (MH+).
EXAMPLE DDD86478
2,6-Dichloro-N-(1 -methyl-1 H-pyrazol-4-yl)-4-(2-piperazin-1 -yl-pyridin-4-yl)- benzenesulfonamide
Prepared from the sulphonamide of intermediate 31 (96mg, 0.25mmol), 2-(1- piperazinyl)pyridine-4-boronic acid pinacol ester (80mg, 0.28mmol), tribasic potassium phosphate (60mg, 0.28mmol), and Pd(PPh3)4 (30mg, 0.026mmol) in DMF (1.6ml) and water (0.6ml), according to the method of intermediate 11 , to give the title compound as a yellow solid (87mg, 0.19mmol, 74%). δH (D-6 DMSO1 300K) 8.19 (1 H, d J 5.2Hz), 7.99
(2H, s), 7.49 (1 H, s), 7.14 (1 H, s), 7.13 (1 H, s), 7.02 (1 H1 d J 5.2Hz), 3.70 (3H, s), 3.54
(4H, m), 2.83 (4H1 m). m/z (ES+, 70V) 467.1 (MH+).
EXAMPLE DDD86479
3,5-Dichloro-3'-piperazin-1 -yl-biphenyl-4-sulfonic acid (1 ,3,5-trimethyl-i H-pyrazol-
4-yl)-amide
Prepared from the boronic ester of intermediate 35 (115mg, 0.25mmol), 1-(3- bromophenyl)piperazine (72mg, 0.48mmol), tribasic potassium phosphate (72mg,
0.34mmol), and Pd(PPh3J4 (30mg, 0.026mmol) in DMF (1.6ml) and water (0.4ml), according to the method of intermediate 11 , to give the title compound as a yellow solid (21 mg, 0.042mmol, 17%). δH (CDCI3, 300K) 7.67 (2H, s), 7.39 (1 H, t J 7.8Hz), 7.04 (3H, m), 3.70 (3H, s), 3.25 (4H1 m), 3.09 (4H, m), 2.19 (3H, s), 1.81 (3H, s). m/z (ES+, 70V) 494.1 (MH+).
EXAMPLE DDD8648Q
2,6-Dichloro-N-(2-methyl-pyridin-3-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)- benzenesulfonamide
Prepared from the sulphonamide of intermediate 9 (100mg, 0.25mmol), 2-(1- piperazinyl)pyridine-4-boronic acid pinacol ester (87mg, 0.30mmol), tribasic potassium phosphate (180mg, 0.85mmol), and Pd(PPh3)4 (30mg, 0.026mmol) in DMF (1.6ml) and water (0.6ml), according to the method of intermediate 11, to give the title compound as a tan coloured solid (37mg, 0.077mmol, 31%). δH (D-6 DMSO, 300K) 8.18 (1 H, d J 5.3Hz), 7.78 (2H, s), 7.64 (1H, d J 4.5Hz), 7.31 (1H, d J 7.7Hz), 7.15 (1H, s), 7.13 (1H, s), 7.02 (1H, d J 4.7Hz), 6.79 (1H, dd J 8.1Hz 4.6Hz), 3.70 (4H, m), 3.05 (4H, m), 2.29 (3H, s). m/z (ES+, 70V) 478.1 (MH+).
EXAMPLE DDD86481
2,6-Dichloro-N-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)-4-(2-piperazin-1-yl-pyridin- 4-yl)-benzenesulfonamide
Prepared from the sulphonamide of intermediate 23A (115mg, 0.25mmol), 2-(1- piperazinyl)pyridine-4-boronic acid pinacol ester (80mg, 0.28mmol), tribasic potassium phosphate (60mg, 0.28mmol), and Pd(PPh3)4 (30mg, 0.026mmol) in DMF (1.6ml) and water (0.4ml), according to the method of intermediate 11 , to give the title compound as a yellow solid (73mg, 0.14mmol, 54%). δH (D-6 DMSO, 300K) 8.20, (1H, d J 5.2Hz), 8.06 (2H, s), 7.15 (1 H, s), 7.02 (1 H, d J 5.2 Hz), 3.60 (3H, s), 3.52 (4H, m), 2.80 (4H, m), 1.98 (3H, s), 1.92 (2H, d J 7.3Hz), 1.70 (1 H1 m), 0.70 (6H, d J 6.6Hz). m/z (ES+, 70V) 537.2 (MH+).
EXAMPLE DDD87748
(34-[2-(3-Methyl-piperazin-1 -yl)-pyridin-4-yl]-N-(1 ,3,5-trimethyM H-pyrazol-4-yl)- benzenesulfonamide
Prepared from the compound of intermediate 11 (250mg, 0.66mmol) and 2-methyl piperazine (500mg, δ.Ommol) in EtOH (0.75ml) according to the method of DDD86213 to give the title compound as a white powder (157mg, 0.36mmol, 55%). δH (D-6 DMSO,
300K) 9.21 (1 H, s), 8.23 (1 H, d J 5.2Hz), 8.01 (2H, d J 8.4Hz), 7.74 (2H, d J 8.4Hz)1 7.13 (1H, s), 7.00 (1 H, d J 5.2Hz), 4.28 (2H, t J 13.3Hz), 3.60 (3H, s), 3.00 (1H, d J 9.6Hz), 2.80-2.68 (3H, m), 2.39 (1 H, t J 11.3Hz), 1.88 (3H, s), 1.63 (3H, s), 1.08 (3H, d J 6.2Hz). m/z (ES+, 70V) 441.2 (MH+).
EXAMPLE DDD87749
4-(3,4,5,6-Tetrahydro-2H-[1,2I]bipyridinyl-4l-yI)-N-(1)3,5-trimethyl-1H-pyrazol-4-yl)- benzenesulfonamide
Prepared from the compound of intermediate 11 (250mg, 0.66mmol) and piperidine (500mg, 5.7mmol) in EtOH (0.75ml) according to the method of DDD86213 to give the title compound as a white powder (189mg, 0.44mmol, 67%). δH (D-6 DMSO, 300K) 9.20 (1H, s), 8.19 (1H, d J 5.2Hz), 7.96 (2H, d J 8.4Hz), 7.74 (2H, d J 8.4Hz), 7.13 (1H, s), 6.96 (1 H, d J 5.2Hz), 3.68-3.62 (4H, m), 3.61 (3H, s), 1.87 (3H, s), 1-70-1.55 (6H, M), 1.63 (3H, s). m/z (ES+, 70V) 426.2 (MH+).
EXAMPLE DDD87751
3'-(2-Hydroxy-ethyl)-biphenyl-4-sulfonic acid (1 ,3,5-tιϊmethyl-1 H-pyrazol-4-yl)- amide
Prepared from the sulphonamide of Intermediate 1 (LOg, 2.91 mmol), 3- hydroxyethylphenyl boronic acid (579mg, 3.49mmol), tribasic potassium phosphate (740mg, 3.49mmol), Pd(dppf)CI2.DCM (119mg, 0.146mmol) and water (2.0ml) in oxygen- free DMF (10.0ml) at 1300C for 1h according to the method of intermediate 11 , to give the title compound as a colourless solid (500mg, 1.30mmol, 45%). δH (CDCI3, 300K) 7.78 (2H, d J 8.3Hz), 7.68 (2H, d J 8.4Hz), 7.49-7.47 (2H, m), 7.43 (1 H, t J 8.4Hz), 7.30 (1 H, d J 7.4Hz), 5.79 (1 H, s br), 3.93 (2H, q J 6.3Hz), 3.68 (3H, s), 2.96 (3H, t J 6.5Hz), 2.09 (3H, s), 1.61 (3H, s), 1.44 (1 H, t J 5.8Hz). m/z (ES+, 70V) 386.2 (MH+).
EXAMPLE DDD87753
3'-[2-(4-Methyl-piperazin-1 -yl)-ethyl]-biphenyl-4-sulfonic acid (1 ,3,5-trimethyM H- pyrazol-4-yl)-amide The compound of example DDD87751 (400mg, 1.04mmol) and triethylamine (218μl, 158mg, 1.56mmol) in DCM (3.0ml) at rt was treated dropwise with methanesulfonylchloride (97μl, 143mg, 1.25mmol) and the reaction stirred for 21 h. The mixture was then diluted with DCM (40.0ml) and the organic layer washed with H2O (2 x 10 ml), dried over MgSO4 and concentrated in vacuo to yield the crude methansulfonate intermediate as an off-white solid (460mg, 0.99mmol, 95%). δH (CDCI3, 300K) 7.81 (2H, d J 8.6Hz), 7.67 (2H, d J 8.6Hz), 7.52-7.42 (3H, m), 7.33-7.26 (1H, m), 5.76 (1H, s br), 4.48 (2H, t J 6.9Hz), 3.69 (3H, s), 3.15 (2H, t J 6.5Hz), 2.92 (3H, s), 2.10 (3H, s), 1.55 (3H1 s). m/z (ES+, 70V) 464.1 (MH+).
A mixture of the above methanesulfonate (150mg, 0.32mmol), sodium carbonate (102mg, 0.96mmol) and N-methyl piperazine (106μl, 96mg, 0.96mmol) in CH3CN (2.0ml) was heated in a microwave at 1200C for 30min. The crude mixture was then filtered through an SCX-2 column which was washed with DCM:MeOH (10:1 , 20.0ml), followed by elution with 7M NH3 in MeOH (20.0 ml). The eluted fraction was concentrated in vacuo and subjected to chromatography (4-10% MeOH:DCM) to give the title compound as a colourless solid (90mg, 0.21 mmol, 50%). δH (CDCI3, 300K) 7.78 (2H, d J 8.5Hz), 7.67 (2H, d J 8.5Hz), 7.49-7.47 (2H, m), 7.45-7.43 (2H, m), 7.40 (1 H, t J 7.40Hz), 7.28 (1 H, s br), 5.79 (1H, s br), 3.68 (3H, s), 2.89 (2H, t J 7.7Hz), 2.66 (2H, t J 8.4Hz), 2.65- 2.32 (4H, m), 2.33 (3H, S br), 2.09 (3H, s), 1.60 (7H, s br). m/z (ES+, 70V) 468.2 (MH+).
EXAMPLE DDD87754 3'-(3-Phenyl-piperazin-1 -ylmethyl)-biphenyl-4-sulfonic acid (1 ,3,5-trimethyl-1 H- pyrazol-4-yl)-amide
Prepared from the aldehyde of intermediate 14 (200mg, 0.54mmol), 2-phenylpiperazine (262mg, 1.62mmol) and sodium triacetoxyborohydride (343mg, 1.62mmol) in CHCI3 (12.0ml) at 500C for 24h according to the method of example DDD86212 to give the title compound as a white solid (200mg, 0.39mmol, 72%). δH (CDCI3, 300K) 7.78 (2H, d J 8.5Hz), 7.69 (2H, d J 8.5Hz), 7.58 (1 H, s br), 7.49 (1 H, d J 7.4Hz), 7.42 (2H, t J 7.5Hz), 7.38 (2H, dd J 1.5Hz 7.3Hz), 7.31 (2H, t J 7.1Hz) 7.27 (1H, t J 1.3Hz), 5.80 (1H, s br), 3.93 (1 H, dd J 2.3Hz 10.0Hz), 3.69 (3H, s), 3.63 (2H, s), 3.14-3.08 (2H, m), 2.94 (1 H, d J 10.6Hz), 2.89 (1H, d J 11.1Hz), 2.42 (1 H, s br), 2.28 (1 H, dt 3.5Hz 7.4Hz), 2.16 (1 H, t J 10.7Hz), 2.09 (3H, s), 1.61 (3H, s). m/z (ES+, 70V) 515.2 (MH+).
EXAMPLE DDD87755
N-(3-Hydroxy-propyl)-4-(2-piperazin-1-yl-pyridin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-
4-yl)-benzenesulfonamide Prepared from the sulphonamide of intermediate 21 (300mg, 0.7mmol), 2-(1-
_piperazinyl)pyridine-4-boronic acid pinacol ester (216mg, 0.7mmol), tribasic potassium phosphate (158mg, OJmmol), Pd(PPh3J4 (50mg, 0.04mmol) and water (1.0ml) in oxygen-free DMF (5.0ml) at 1300C for 1h, according to the method of intermediate 11 except with the use of Pd(PPh3)4 as reaction catalyst, to give the title compound as a white solid (100mg, 0.2mmol, 26%). δH (D-6 DMSO, 300K) 9.36 (2H, s br), 8.26 (1 H, d J 5.6Hz), 8.08 (2H, d J 8.4Hz), 7.81 (2H, d J 8.4Hz), 7.43 (1 H1 s), 7.23 (1H, d J 5.6Hz), 3.99-3.92 (4H, m), 3.68-3.63 (1H1 m), 3.63 (3H, s), 3.46-3.41 (3H, m), 3.27-3.21 (4H, m), 1.89 (3H, s), 1.57 (3H, s), 1.58-1.52 (2H, m). m/z (ES+, 70V) 485.2 (MH+).
EXAMPLE DDD87756 4-[2-(3-Phenyl-piperazϊn-1-yl)-pyridin-4-yl]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)- benzenesulfonamide
Prepared from the compound of intermediate 11 (250mg, 0.66mmol) and 2-phenyl piperazine (500mg, 3.1mmol) in EtOH (0.75ml) according to the method of DDD86213 to give the title compound as a white powder (182mg, 0.36mmol, 55%). δH (D-6 DMSO, 300K) 9.24 (1H, s br), 8.25 (1 H, d J 5.2Hz), 8.01 (2H, d J 8.4Hz), 7.73 (2H, d J 8.4Hz), 7.54 (2H, d J 7.4Hz), 7.41 (2H, t J 7.35Hz), 7.34 (1H, t J 7.35Hz), 7.18 (1H, s), 7.03 (1H, d J 5.3Hz), 4.42-4.39 (3H1 m), 3.81-3.78 1 H, m), 3.60 (3H, s), 3.14 (1 H, d J 8.8Hz), 2.93- 2.89 (3H, m), 2.70 (1 H, t J 11.8Hz), 1.87 (3H, s), 1.63 (3H, s). m/z (ES+, 70V) 503.1 (MH+).
EXAMPLE DDD87758
2'-Diethylaminomethyl-biphenyl-4-sulfonic acid (1 ,3,5-trimethyM H-pyrazol-4-yl)- amide
Prepared from the aldehyde of intermediate 17 (150mg, 0.41 mmol), diethylamine (127μl, 90mg, 1.23mmol) and sodium triacetoxyborohydride (261 mg, 1.23mmol) in CHCI3 (10.0ml) at 5O0C for 24h according to the method of example DDD86212 to give the title compound as a white solid (106mg, 0.25mmol, 62%). δH (CDCI3, 300K) 7.76 (2H, d J 8.2Hz), 7.63 (1H, s br), 7.47 (2H, d J 8.4Hz), 7.38 (1 H, t J 7.0Hz), 7.31 (1H, t J 7.1 Hz), 7.15 (1 H, d J 7.7Hz)1 5.79 (1 H, s br), 3.69 (3H, s), 3.41 (2H1 m), 2.40 (4H, d J 5.6Hz), 2.13 (3H, s), 1.63 (3H, s), 0.90 (6H, t J 6.5Hz). m/z (ES+, 70V) 427.2 (MH+).
EXAMPLE DDD87759
2'-Pyrrolidin-1-ylmethyl-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)- amide Prepared from the aldehyde of intermediate 17 (150mg, 0.41 mmol), pyrrolidine (101μl, 87mg, 1.23mmol) and sodium triacetoxyborohydride (261 mg, 1.23mmol) in CHCI3 (10.0ml) at 500C for 24h according to the method of example DDD86212 to give the title compound as a white solid (166mg, 0.39mmol, 95%). δH (CDCI3, 300K) 7.78 (2H, d J 8.2Hz), 7.54 (3H, d J 7.3Hz), 7.41 (1H, d J 5.9Hz), 7.35 (1H1 m), 7.21 (1H, d J 7.5Hz), 5.81 (1 H1 s br), 3.69 (3H, s), 3.55 (2H, s br), 2.45 (4H, s br), 2.13 (3H, s br), 1.76 (4H, s br), 1.62 (3H1 s). m/z (ES+, 70V) 454.1 (MH+). EXAMPLE DDD87761
4-[2-(3,5-Dimethyl-piperazin-1 -yl)-pyridin-4-yI]-N-(1 ,3,5-trimethyl-1 H-pyrazol-4-yl)- benzenesulfonamide Prepared from the compound of intermediate 11 (250mg, 0.66mmol) and 2,6- dimethylpiperazine (>95% syn isomer, 500mg, 4.38mmol) in EtOH (0.75ml) according to the method of DDD86213 to give the title compound as a white powder (211mg, 0.46mmol, 70%). δH (D-6 DMSO, 300K) 9.22 (1 H, s), 8.18 (1 H, d J 4.0Hz), 7.97 (2H, d J 7.7Hz), 7.70 (2H, d J 7.7Hz), 7.10 (1H, s), 6.95 (1H, s), 4.30 (2H, d J 11.8Hz), 3.56 (3H, s), 2.76 (2H, s br), 2.26 (2H, t J 11.3Hz), 1.84 (3H, s), 1.59 (3H, s), 1.04 (6H1 d J 4.8Hz). m/z (ES+, 70V) 455.2 (MH+).
EXAMPLE DDD87763
N-Methyl-4-(2-piperazin-1 -yl-pyιϊdin-4-yl)-N-(1 ,3,5-trimethyM H-pyrazol-4-yl)- benzenesulfonamide
Prepared from the sulphonamide of Intermediate 18 (250mg, 0.7mmol), 2-(1- piperazinyl)pyridine-4-boronic acid pinacol ester (202mg, 0.7mmol), tribasic potassium phosphate (148mg, OJmmol), Pd(PPh3)4 (50mg, 0.04mmol) and water (1.0ml) in oxygen-free DMF (5.0ml) at 1300C for 1 h, according to the method of intermediate 11 except with the use of Pd(PPh3)4 as reaction catalyst, to give the title compound as a white solid (148mg, 0.3mmol, 48%). δH (CDCI3, 300K) 8.28 (1 H, d, J 3.8Hz), 7.79 (2H, d, J 7.2Hz), 7.71 (2H, d, J 7.2Hz), 6.82 (1 H, d, J 3.8Hz), 6.79 (1 H, s), 3.69 (3H, s), 3.57- 3.61 (4H, m), 3.21 (3H, s), 2.99-3.04 (4H, m), 2.13 (3H, s), 1.55 (3H, s). m/z (ES+, 70V) 441.2 (MH+).
EXAMPLE DDD87764
2'-(4-Methyl-piperazin-1-ylmethyl)-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H- pyrazol-4-yl)-amide
Prepared from the aldehyde of intermediate 17 (150mg, 0.41 mmol), N-methylpiperazine (136μl, 123mg, 1.23mmol) and sodium triacetoxyborohydride (261 mg, 1.23mmol) in CHCI3 (10.0ml) at 500C for 24h according to the method of example DDD86212 to give the title compound as a colourless solid (150mg, 0.33mmol, 81%). δH (CDCI3, 300K) 7.75 (2H, d J 8.4Hz)1 7.58 (2H, d J 8.3Hz)1 7.45 (1 H1 d J 5.9Hz), 7.39-7.33 (2H, m), 7.22 (1H, dd J 1.6Hz 7.3Hz), 5.79 (1H, s br), 3.69 (3H, s), 3.33 (2H, s), 2.42 (4H, s br), 2.31 (3H, s br), 2.11 (3H1 s), 1.98 (4H, s br), 1.64 (3H, s). m/z (ES+, 70V) 454.1 (MH+). EXAMPLE DDD87765
3'-{Benzylamino-methyl)-biphenyl-4-sulfonic acid (1 ,3,5-trimethyl-1 H-pyrazol-4-yl)- amide
Prepared from the aldehyde of intermediate 14 (200mg, 0.54mmol), benzylamine (176μl, 173mg, 1.62mmol) and sodium triacetoxyborohydride (343mg, 1.62mmol) in CHCI3
(12.0ml) at 500C for 24h according to the method of example DDD86212 to give the title compound as a white solid (105mg, 0.23mmol, 42%). δH (CDCI3, 300K) 7.78 (2H, d J
8.4Hz), 7.69 (2H, d J 8.4Hz), 7.60 (1 H, s br), 7.50 (1H1 d J 7.5Hz), 7.44 (1 H, t J 7.5Hz),
7.40 (1H, d J 7.6Hz), 7.35 (4H, d J 4.8Hz), 7.29-7.28 (1 H, m), 5.85 (1 H, s br), 3.90 (2H, s br), 3.86 (2H, s br), 3.68 (3H, s), 2.08 (3H, s), 1.62 (3H, s). m/z (ES+, 70V) 461.1 (MH+).
EXAMPLE DDD87767
4-(2-t1,4]Diazepan-1-yl-pyridin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)- benzenesulfonamide Prepared by heating the compound of intermediate 11 (250mg, 0.66mmol) and homopiperazine (500mg, δ.Ommol) in EtOH (1.0ml) at 155°C for 2h, according to the method of DDD86213 to give the title compound as a white powder (207mg, 0.47mmol, 71%). δH (D-6 DMSO, 300K) 8.20 (1 H, d J 5.8Hz), 7.99 (2H, d J 8.5Hz), 7.75 (2H, d J 8.5Hz), 6.90 (1H1 s), 6.89 (1 H, d J 5.8Hz), 3.80 (2H, t J 6.1 Hz), 3.75 (2H, t J 5.8Hz), 2.92 (2H, t J 5.2Hz), 2.72 (2H, t J 5.6Hz), 1.88 (3H, s), 1.83 (2H, p J 5.6Hz), 1.63 (3H, s). m/z (ES+, 70V) 441.2 (MH+).
EXAMPLE DDD87768
3'-Piperidin-4-yl-biphenyl-4-sulfonic acid (1 ,3,5-trimethyl-1 H-pyrazol-4-yl)-amide Prepared from the sulphonamide of intermediate 32 (500mg, 1.28mmol), 4-(3- bromophenyl)piperidine hydrochloride (425mg, 1.54mmol), tribasic potassium phosphate (652mg, 3.0mmol), and Pd(dppf)CI2.DCM (100mg, 0.12mmol) in DMF (3.0ml) and water (0.75ml), according to the method of intermediate 11 , to give the title compound as an off-white powder (350mg, 0.82mmol, 64%). δH (D-6 DMSO, 300K) 7.90 (2H, d J 8.4Hz), 7.71 (2H, d 8.4Hz), 7.61 (1H, s), 7.58 (1 H, d J 7.9Hz), 7.46 (1 H, t J 7.7Hz), 7.33 (1 H, d J 7.7Hz), 3.58 (3H, s), 3.10-3.07 (2H, m br), 2.70 (1 H, tt J 12.1Hz 3.3Hz)1 2.63 (2H1 td 10.8Hz 1.8Hz)1 1.85 (3H1 s), 1.79-1.73 (2H, m br), 1.63 (3H, s), 1.62 (qd J 12.2Hz 3.8Hz). m/z (ES+, 70V) 425.2 (MH+).
EXAMPLE DDD87769 2,6-Dichloro-4-[3-(4-methyl-piperazin-1 -yl)-propyl]-N-(1 ,3,5-tιϊmethyM H-pyrazol-4- yl)-benzenesulfonamide
The alkyne of example DDD86469 (65mg, 0.14mmol) and 10% w/w palladium on charcoal (13mg, 20wt%) in MeOH (7.0ml) was stirred at rt under for 1.5h. The mixture was filtered through a celite pad, the filter cake washed with DCM:MeOH (1:1 , 2 x 10 ml), the combined filtrates concentrated in vacuo and subjected to chromatography (4-10 %
MeOH/DCM) to give the title compound as a white solid (28mg, 0.059mmol, 42%). δH
(CDCI3, 300K) 7.29 (2H, s), 6.58 (1 H1 s), 3.66 (3H1 s), 2.63 (2H, s br), 2.47 (6H, s), 2.31
(3H, S), 2.16 (3H, s) 1.79 (2H, s br), 1.72 (3H1 s), 1.59 (4H, s br). m/z (ES+, 70V) 474.1 (MH+).
EXAMPLE DDD87993
2,6-Dichloro-N-(1,5-dimethyl-1H-pyrazol-4-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)- benzenesulfonamide Prepared from the sulphonamide of intermediate 27 (100mg, 0.25mmol), 2-(1- piperazinyl)pyridine-4-boronic acid pinacol ester (80mg, 0.28mmol), tribasic potassium phosphate (60mg, 0.28mmol), and Pd(PPh3)4 (30mg, 0.026mmol) in DMF (1.6ml) and water (0.6ml), according to the method of intermediate 11 , to give the title compound as a yellow solid (32mg, 0.07mmol, 27%). δH (D-6 DMSO, 300K) 8.20 (1 H1 d J 5.2Hz), 8.02 (2H, s), 7.20 (1 H, s), 7.04 (1 H, d J 5.2Hz), 7.02 (1 H, s), 3.64 (3H, s), 3.54 (4H, m), 2.82 (4H, m), 2.06 (3H, s). m/z (ES+, 70V) 481.1 (MH+).
EXAMPLE DDD87994 N-(2-Methyl-pyridin-3-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)-benzenesulfonamide Prepared from the sulphonamide of intermediate 8 (82mg, 0.25mmol), 2-(1- piperazinyl)pyridine-4-boronic acid pinacol ester (80mg, 0.28mmol), tribasic potassium phosphate (60mg, 0.28mmol), and Pd(PPh3)4 (30mg, 0.026mmol) in DMF (1.6ml) and water (0.6ml), according to the method of intermediate 11, to give the title compound as a yellow solid (13mg, 0.03mmol, 13%). δH (D-6 DMSO, 300K) 8.20 (1 H, d J 5.3Hz), 8.01 (1 H, d J 4.2Hz), 7.90 (2H, d J 8.3Hz), 7.75 (2H, d J 8.3Hz), 7.36 (1H, dd J 8.1Hz 1.1Hz), 7.11 (1 H, s), 7.03 (1 H, dd J 8.0Hz 4.8Hz), 6.99 (1 H, d J 5.2Hz), 3.62 (4H, m), 2.96 (4H, m), 2.21 (3H, s). m/z (ES+, 70V) 410.2 (MH+).
EXAMPLE DDD87995 N-(1,5-Dimethyl-1H-pyrazol-4-y|)-4-(2-piperazin-1-yl-pyridin-4-yl)- benzenesulfonamide Prepared from the sulphonamide of intermediate 27 (83mg, 0.25mmol), 2-(1- piperazinyl)pyridine-4-boronic acid pinacol ester (80mg, 0.28mmol), tribasic potassium phosphate (60mg, 0.28mmol), and Pd(PPh3)4 (30mg, 0.026mmol) in DMF (1.6ml) and water (0.6ml), according to the method of intermediate 11 , to give the title compound as a yellow solid (22mg, 0.05mmol, 21 %). δH (D-6 DMSO, 300K) 8.21 (1 H1 d J 5.2Hz), 7.96 (2H, d J 8.4Hz), 7.75 (2H, d 8.4Hz), 7.09 (1H, s), 6.98 (1H, d J 5.2Hz), 6.91 (1H, s), 4.13 (1H, s br), 3.63 (3H, s), 3.52 (4H, m), 2.82 (4H, m), 1.92 (3H, s). m/z (ES+, 70V) 413.2 (MH+).
EXAMPLE DDD87997
2,5-Difluoro-4-(2-piperazin-1-yl-pyridin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)- benzenesulfonamide
Prepared from Intermediate 4 (200mg, O.δmmol), 2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (152mg, O.δmmol), tribasic potassium phosphate (112mg, O.δmmol), Pd(PPh3)4 (45mg, 0.04mmol) and water (0.8ml) in oxygen-free DMF (4.0ml) at 1300C for 1 h, according to the method of intermediate 11 except with the use of Pd(PPh3)4 as reaction catalyst, to give the title compound as a white solid (93mg, 0.2mmol, 38%). δH (CDCI3, 300K) 8.28 (1 H, d J 5.1Hz), 7.52 (1H, dd J 5.7Hz 9.1Hz), 7.34 (1H, dd J 5.6Hz 9.8Hz), 6.74-6.70 (2H, m), 3.68 (3H, s), 3.59-3.54 (4H, m), 3.03-2.99 (4H, m), 2.18 (3H, s), 1.81 (3H, s). m/z (ES+, 70V) 463.2 (MH+).
EXAMPLE DDD87999
4-[3-(4-Methyl-piperazin-1-yI)-prop-1-ynyl]-N-(1,3,5-trimethyl-1 H-pyrazol-4-yl)- benzenesulfonamide Prepared from the sulphonamide of intermediate 1 (526mg, 1.53mmol), 1-methyl-4-prop- 2-ynyl-piperazine (253mg, 1.83mmol), CuI (15mg, 0.077mmol) and Pd(PPh3)4 (89mg, 0.077mmol), in DMF (3.0ml) and NEt3 (2.0ml) according to the method of intermediate 36, to give the title compound as an off-white solid (390mg, 0.97mmol, 64%). δH (CDCI3, 300K) 7.66 (2H, d J 7.2Hz),7.47 (2H, d J 7.6Hz)1 5.85 (1 H, s br), 3.67 (3H, s), 3.67 (3H, s), 3.58 (2H, s), 2.84 (4H, s br), 2.48 (4H, s br), 2.03 (3H, s br), 1.64 (3H, s br), 1.52 (3H, s). m/z (ES+, 70V) 402.1 (MH+).
EXAMPLE DDD88000
6-[2-(1 -Methyl-piperidin-4-yl)-ethylamino]-pyridine-3-sulfonic acid (1 ,3,5-trimethyl- 1 H-pyrazol-4-yl)-amide Prepared from the sulphonamide of intermediate 5 (528mg, 1.8mmol) and 2-(1- methylpiperidin-4-yl)ethanamine (500mg, 3.5mmol) according to method 1 of EXAMPLE86213, to give the title compound as a white solid (190mg, O.δmmol, 27%). δH (CDCI3, 300K) 8.38 (1 H, d, J 2.3Hz), 7.60 (1 H, dd J 2.3Hz 9.0Hz), 6.31 (1 H, d J 9.0Hz), 5.80 (1H, s), 4.97 (1 H, bs), 3.68 (3H, s), 3.38-3.32 (2H, m), 2.87-2.81 (2H, m), 2.26 (3H, s), 2.12 (3H, s), 1.93-1.85 (2H, m), 1.73 (3H, s), 1.74-1.68 (2H, m), 1.63-1.54 (3H, m), 1.31-1.37 (2H, m). m/z (ES+, 70V) 407.2 (MH+)
EXAMPLE DDD88002 N-(3,5-Dimethyl-isoxazol-4-yI)-4-(2-piperazin-1 -yl-pyridin-4-yl)-benzenesulfonamide Prepared from the sulphonamide of intermediate 6 (83mg, 0.25mmol), 2-(1- piperazinyl)pyridine-4-boronic acid pinacol ester (80mg, 0.28mmol), tribasic potassium phosphate (60mg, 0.28mmol), and Pd(PPh3)4 (30mg, 0.026mmol) in DMF (1.6ml) and water (0.4ml), according to the method of intermediate 11 , to give the title compound as a tan coloured solid (11mg, 0.03mmol, 11%). δH (D-6 DMSO, 300K) 8.20, (1H, d J 5.3Hz), 7.99 (2H, d J 8.4Hz), 7.75 (2H, d J 8.4Hz), 7.10 (1 H, s), 6.98 (1 H, dd J 5.2Hz 1.1 Hz), 3.53 (4H, m), 2.83 (4H, m), 1.93 (3H, m), 1.80 (3H, s). m/z (ES+, 70V) 482.1 (MH+).
EXAMPLE DDD88003
3'-Piperidin-4-yl-biphenyl-4-sulfonic acid {2-methyl-pyridin-3-yl)-amide
Prepared from the sulphonamide of intermediate 33 (230mg, 0.62mmol), 4-(3- bromophenyl)piperidine hydrochloride (204mg, 0.74mmol), tribasic potassium phosphate (313mg, 1.48mmol), and Pd(dppf)CI2.DCM (50mg, 0.06mmol) in DMF (3.0ml) and water (1.OmI), according to the method of intermediate 11 , to give the title compound as an off- white powder (67mg, 0.16mmol, 26%). δH (CDCI3, 300K) 8.35 (1 H, dd J 1.3Hz 4.7Hz), 7.76 (2H, d J 8.5Hz), 7.75 (1 H, m), 7.43-7.38 (3H, m), 7.28 (1 H, m), 7.15 (1 H, dd J 4.7Hz 8.0Hz), 3.23-3.18 (2H, m), 2.76 (2H, td J 2.1 Hz 12.1 Hz), 2.68 (1 H, tt J 3.6Hz 12.1 Hz), 2.22 (3H, s), 1.89-1.83 (2H, m br), 1.69 (2H1 qd J 12.1 Hz 3.9Hz). m/z (ES+, 70V) 408.2 (MH+).
EXAMPLE DDD88005
3'-Dimethylaminomethyl-biphenyl-4-sulfonic acid (1 ,3,5-trimethyM H-pyrazol-4-yl)- amide Prepared from the aldehyde of intermediate 14 (150mg, 0.41 mmol), 2M dimethylamine solution in THF (615ml, 1.23mmol) and sodium triacetoxyborohydride (261 mg, 1.23mmol) in CHCI3 (10.0ml) at 50°C for 24h according to the method of example DDD86212 to give the title compound as a white solid (146mg, 0.37mmol, 90%). δH (CDCI3, 300K) 7.78 (2H, d J 6.9Hz), 7.70 (2H, d J 7.5Hz), 7.60 (1H, s br), 7.49 (1H, d J 6.8Hz), 7.42 (1 H, t J 7.8Hz), 7.36 (1H, d J 6.7Hz), 5.81 (1 H, s br), 3.68 (3H, s), 3.59 (2H, s), 2.33 (6H, s), 2.08 (3H, s), 1.62 (3H, s). m/z (ES+, 70V) 399.3 (MH+).
EXAMPLE DDD88006
3'-lmidazol-1-ylmethyl-biphenyl-4-sulfonic acid (1,3,5-trimethyl-1H-pyrazol-4-yl)- amide Prepared from the boronic ester of intermediate 32 (157mg, 0.38mmol), 1-(3- bromobenzyl)-1 H-imidazole (114mg, 0.48mmol), tribasic potassium phosphate (144mg, 0.68mmol), and Pd(PPh3)4 (48mg, 0.042mmol) in DMF (1.6ml) and water (0.4ml), according to the method of intermediate 11 , to give the title compound as a white solid (157mg, 0.37mmol, 93%). δH (D-6 DMSO, 300K) 7.84 (3H, m), 7.73-7.60 (4H, m), 7.59 (1 H, m), 7.50 (1H, t J 7.7Hz), 7.30 (1 H, d J 7.7Hz), 7.27 (1 H, s), 6.92 (1H, s), 5.28 (2H, s), 3.56 (3H, s), 1.82 (3H, s), 1.59 (3H, s). m/z (ES+, 70V) 422.2 (MH+).
EXAMPLE DDD88007
3,5-Dichloro-3'-diethylaminomethyl-biphenyl-4-sυlfonic acid (1 ,3,5-trimethyl-1 H-pyrazol-4- yl)-amide
Prepared from the sulphonamide of intermediate 15 (210mg, 0.52mmol), diethylamine (0.25ml), sodium triacetoxyborohydride (220mg, 1.04mmol) in chloroform (3.0ml), according to the method of example DDD85612, to give the title compound as an off- white powder (39mg, O.Oδmmol, 15%). δH (CDCI3, 300K) 7.65 (2H, s), 7.53 (1 H, s), 7.43- 7.37 (3H, m), 6.62 (1H, s), 3.64 (3H, s), 3.60 (2H, s), 2.52 (4H, q J 6.8Hz), 2.14 (3H, s), 1.77 (3H, s), 1.03 (6H, t J 6.8Hz). m/z (ES+, 70V) 495.1 (MH+).
EXAMPLE DDD88009
3,5-Dichloro-3'-pyrrolidin-1-ylmethyl-biphenyl-4-sulfonic acid (1 ,3,5-trimethyl-1 H-pyrazol-4- yl)-amide
Prepared from the sulphonamide of intermediate 15 (210mg, 0.52mmol), pyrolidine (0.25ml) and sodium triacetoxyborohydride (220mg, 1.04mmol) in chloroform (3.0ml), according to the method of example DDD85612, to give the title compound as an off- white powder (172mg, 0.35mmol, 67%). δH (CDCI3, 300K) 7.65 (2H, s), 7.52 (1H, s), 7.45-7.37 (3H, m), 6.72 (1 H, s br), 3.67 (2H1 s), 3.64 (3H, s), 2.50 (4H, s br), 2.12 (3H, s), 1.77 (4H, s br), 1.73 (3H, s). m/z (ES+, 70V) 493.1 (MH+). EXAMPLE DDD88186
2-Methyl-4-(2-piperazin-1 -yl-pyridin-4-yI)-N-(1 ,3,5-trimethyl-1 H-pyrazol-4-yl)- benzenesulfonamide Prepared from the sulphonamide of intermediate 20 (90mg, 0.25mmol), 2-(1- piperazinyl)pyridine-4-boronic acid pinacol ester (80mg, 0.28mmol), tribasic potassium phosphate (60mg, 0.28mmol), and Pd(PPh3)4 (30mg, 0.026mmol) in DMF (1.6ml) and water (0.6ml), according to the method of intermediate 11 , to give the title compound as a yellow solid (47mg, O.Hmmol, 43%). δH (D-6 DMSO, 300K) 8.20 (1H, d J 5.1Hz), 7.84 (1 H, s), 7.70 (1 H1 dd J 8.3Hz 1.5Hz), 7.64 (1 H, d J 8.3Hz), 7.10 (1 H, s), 6.99 (1 H, dd J 5.2Hz 1.2Hz), 3.55 (7H, m), 2.87 (4H, m), 2.65 (3H, s), 1.84 (3H, s), 1.58 (3H, s). m/z (ES+, 70V) 441.2 (MH+).
EXAMPLE DDD88187 5'-(4-Methyl-piperazin-1-ylmethyl)-3'-propoxy-biphenyl-4-sulfonic acid (1,3,5- trimethyl-1H-pyrazol-4-yl)-amide
Prepared from the aldehyde of intermediate 24 (150mg, 0.35mmol), N-methylpiperazine (0.116ml, 105mg, 1.05mmol) and sodium triacetoxyborohydride (223mg, 1.05mmol) in CHCI3 (10.0ml) at 500C for 24h according to the method of example DDD86212 to give the title compound as a white solid (143mg, 0.28mmol, 80%). δH (CDCI3, 300K) 7.76 (2H, d J 8.4Hz), 7.67 (2H, d J 8.4Hz), 7.13 (1 H, s br), 7.00 (1 H, s br), 6.95 (1H, s br), 5.74 (1H, s br), 3.98 (2H, t J 6.6Hz), 3.68 (3H, s), 3.54 (2H, s), 2.49 (4H, s br), 2.30 (3H, s), 2.09 (3H, s), 1.84 (2H, m), 1.60 (7H, s), 1.07 (3H, t J 7.4Hz). m/z (ES+, 70V) 512.2 (MH+).
EXAMPLE DDD88188
2-Fluoro-4-(2-piperazin-1 -yl-pyridin-4-yl)-N-(1 ,3,5-trimethyl-1 H-pyrazol-4-yl)- benzenesulfonamide
Prepared from the sulphonamide of intermediate 10 (91mg, 0.25mmol), 2-(1- piperazinyl)pyridine-4-boronic acid pinacol ester (80mg, 0.28mmol), tribasic potassium phosphate (60mg, 0.28mmol), and Pd(PPh3)4 (30mg, 0.026mmol) in DMF (1.6ml) and water (0.6ml), according to the method of intermediate 11 , to give the title compound as a pale yellow solid (25mg, 0.056mmol, 22%). δH (D-6 DMSO, 300K) 8.03 (1 H, m), 7.57 (2H1 m), 7.46 (1H, d J 7.7Hz), 6.90 (1H, s), 6.81 (1H, m), 3.46 (3H, s), 3.43 (4H, m), 2.78 (4H, m), 1.86 (3H, s), 1.65 (3H, s). m/z (ES+, 70V) 445.2 (MH+) EXAMPLE DDD88189 3'-Piperidin-4-yl-biphenyl-4-sulfonic acid (3,5-dimethyI-isoxazol-4-yl)-amide
Prepared from the sulphonamide of intermediate 34 (151mg, 0.4mmol), 4-(3- bromophenyl)piperidine hydrochloride (133mg, 0.48mmol), tribasic potassium phosphate (144mg, 0.68mmol), and Pd(PPh3)4 (48mg, 0.042mmol) in DMF (3.2ml) and water
(0.8ml), according to the method of intermediate 11 , to give the title compound as a white solid (19mg, 0.046mmol, 12%). δH (D-6 DMSO, 300K) 7.00, (4H, s), 6.76 (1 H, s), 6.74
(1 H, d J 7.7 Hz), 6.64 (1 H, t J 6.6Hz)1 6.53 (1 H, d J 6.9Hz), 2.46 (2H1 d 12.0Hz), 2.05
(3H, m), 1.25 (1H, s), 1.19 (3H, s), 1.15 (2H, m), 1.10 (3H, S)1 0.99 (2H, q, J 12.2Hz). m/z (ES+, 70V) 412.2 (MH+).
EXAMPLE DDD88191
4-[3-(4-Methyl-piperazin-1 -yl)-propyl]-N-(1 ,3,5-trimethyM H-pyrazol-4-yl)- benzenesulfonamide Prepared from the alkyne of example DDD87999 (345mg, 0.86mmol) and 10% w/w palladium on charcoal (70mg, 20wt%) in MeOH (4OmL) for 2 h according to the method of example DDD00087769 to give the title compound as a pale yellow solid (170mg, 0.42mmol, 49%). δH (CDCI3, 300K) 7.63 (2H, d J 8.3Hz), 7.27-7.26 (2H1 m), 5.72 (1 H, s br), 3.67 (3H, s), 2.71 (6H, t J 7.4Hz), 2.44 (6H, m), 2.08 (3H, s), 1.85 (2H, s br), 1.53 (6H, s). m/z (ES+, 70V) 406.2 (MH+).
EXAMPLE DDD00088193
2,6-Dichloro-N-methyl-4-(2-piperazin-1-yl-pyridin-4-yl)-N-(1,3,5-trimethyl-1H- pyrazol-4-yl)-benzenesulfonamide Prepared from the sulphonamide of Intermediate 19 (225mg, O.δmmol), 2-(1- piperazinyl)pyridine-4-boronic acid pinacol ester (153mg, O.δmmol), tribasic potassium phosphate (112mg, 0.5mmol), Pd(PPh3)4 (30mg, 0.03mmol) and water (0.5ml) in oxygen-free DMF (3.0ml) at 1200C for 20min, according to the method of intermediate 11 , to give the title compound as a white solid (173mg, 0.3mmol, 64%). δH (D-6 DMSO1 300K) 9.23 (2H, s br), 8.27 (1H1 d J 5.3Hz), 8.15 (2H1 s), 7.42 (1H1 s), 7.27 (1H, d J 5.3Hz), 3.95-3.89 (4H, m br), 3.60 (3H1 s), 3.36 (3H, s), 3.25-3.19 (4H, m br), 1.97 (3H1 s), 1.76 (3H1 s). m/z (ES+, 70V) 509.1 (MH+).
EXAMPLE DDD88194 3'-lsopropoxy-5'-(4-methyl-piperazin-1-ylmethyl)-biphenyl-4-sulfonic acid (1,3,5- trimethyl-1H-pyrazoI-4-yI)-amide Prepared from the aldehyde of intermediate 25 (150mg, 0.35mmol), N-methylpiperazine (0.116ml, 105mg, 1.05mmol) and sodium triacetoxyborohydride (223mg, 1.05mmol) in CHCI3 (10.0ml) at 500C for 24h according to the method of example DDD86212 to give the title compound as a colourless solid (120mg, 0.23mmol, 67%). δH (CDCI3, 300K) 7.76 (2H, d J 6.9 Hz), 7.66 (2H, d J 7.5 Hz), 7.11 (1H, s br), 6.99 (1 H, s br), 6.94 (1 H, s br), 5.75 (1 H, s br), 4.64 (1 H, s br), 3.68 (3H, s), 3.54 (2H, s), 2.49 (4H, s), 2.31 (3H, s), 2.09 (3H, s), 1.66 (4H, m), 1.61 (3H, s), 1.37 (6H, d J 5.0Hz). m/z (ES+, 70V) 512.2 (MH+).
EXAMPLE DDD88195
3'-Diethylaminomethyl-biphenyl-4-sulfonic acid methyl-(1 ,3,5-trimethyM H-pyrazol- 4-yl)-amide
Prepared from the sulphonamide of intermediate 22 (85mg, 0.2mmol), diethylamine (49mg, 0.7mmol) and sodium triacetoxyborohydride (141 mg, OJmmol) in CHCI3 (4ml), according to the method of Example DDD86212 to give the title compound as a white powder (19mg, 0.043mmol, 22%). δH (D-6 DMSO, 300K) 9.91 (1H, s br), 8.06 (1 H, s), 8.00 (2H, d J 8.5Hz), 7.89-7.86 (1 H, m), 7.81 (2H, d J 8.5Hz), 7.66-7.61 (2H, m), 4.41 (2H, d J 5.6Hz), 3.62 (3H, s), 3.16 (3H, s), 3.17-3.08 (3H, m), 1.92 (3H, s), 1.59 (3H, s), 1.28 (6H, t J 7.3Hz). m/z (ES+, 70V) 441.2 (MH+).
EXAMPLE DDD88196
3'-(4-Methyl-piperazin-1-ylmethyl)-biphenyl-4-sulfonic acid methyl-(1,3,5-trimethyl-
1 H-pyrazol-4-yl)-amide
Prepared from the sulphonamide of intermediate 22 (85mg, 0.2mmol), N- methylpiperizine (67mg, 0.7mmol) and sodium triacetoxyborohydride (141 mg, OJmmol) in CHCI3 (4ml), according to the method of Example DDD86212 to give the title compound as a white powder (65mg, 0.14mmol, 69%). δH (D-6 DMSO, 300K) 8.13 (1 H, s br), 8.02 (2H, d J 7.4Hz), 7.89-7.84 (1 H, m br), 7.79 (2H, d J 7.4Hz), 7.69 (1 H, s br), 7.62 (1H, s br), 4.57-4.34 (2H, m br), 3.62 (3H, s), 3.74-3.56 (4H, m br), 3.52-3.27 (4H, m br), 3.16 (3H, s), 2.83 (3H, s br), 1.91 (3H, s), 1.60 (3H, s). m/z (ES+, 70V) 468.2 (MH+).
EXAMPLE DDD86469
2,6-Dichloro-4-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)- benzenesulfonamide Prepared from the sulphonamide of intermediate 19 (1 .3g, 3.06mmol), 4-(propyn-3- yl)-1-methyl piperazine (1 .05g, 7.61 mmol), CuI (50mg, 0.26mmol) and Pd(PPlIs)4 ClOOmg, 0.08mmol), in DMF (15ml) and NEt3 (8ml) according to the method of intermediate 36, to give the title compound as a white solid (1.25g, 2.66mmol, 87%). δH (CDCI3, 300K) 7.43 (2H, s), 3.67 (3H, s), 3.54 (2H, s), 3.40 (3H, s), 2.73-2.60 (4H, s br), 2.59-2.42 (4H, s br), 2.32 (3H, s), 2.06 (3H, s), 1.83 (3H, s). m/z (ES+, 70V) 470.2 (MH+).
EXAMPLE DDD99837
N-(3-isobutyl-1 ,5-dimethyl-1 H-pyrazol-4-yl)-4-(3-(1 -methylpipeπdin-4- yl)propyl)benzenesulfonamide Prepared from 4-allyl-1 -methylpiperidine (2.18g, 15.6mmol) and the compound of intermediate 41 (2.Og, 5.2mmol) according to the method of compound DDD100096 to give the title compound as a white powder (1.84g, 4.12mmol, 79%). δH (CDCI3, 300K), 7.55 (2H, d J 7.9Hz), 7.19 (2H, d J 7.9Hz), 5.80 (1H, br s), 3.61 (3H, s), 2.76 (2H, m), 2.58 (2H, t J 7.7Hz), 2.19 (3H, s), 2.01 (3H, s), 1.80 (3H, m), 1.62-1.51 (m, 4H), 1.22- 1.11 (4H, m), 0.64 (6H, d J 6.25Hz). m/z (ES+, 70V) 446.2 (MH+).
EXAMPLE DDD100096
2,6"Dichloro-N-(difluoromethyl)-4-(3-(piperidin-4-yl)propyl)-N-(1,3,5-trimethyl-1H- pyrazol-4-yl)benzenesulfonamide hydrochloride salt Prototypical procedure for coupling of an aryl bromide with a 9BBN~derived trialkylborane under Suzuki-Miyaura conditions;
A solution of tert-butyl 4-allylpiperidine-1-carboxylate (293mg, 1.29mmol, prepared according to the methods cited by Billote, S. Synlett, 1998, 4Λ 379-380) in 1.0ml of THF, under argon at rt, was treated dropwise with 9-BBN (0.5M in IHF, 2.6ml, 1.3mmol). The reaction was then heated in a microwave for 30min at 9O0C. The resulting solution was then transferred via cannula into a stirred mixture of the compound of intermediate 40 (300mg, 0.645mmol) and potassium phosphate (272mg, 1.28mmol) in DMF (2.5ml) and water (0.75ml) under argon. After bubbling argon through the reaction for 5min at rt Pd(PPh3)4 (20mg) was added, the reaction vessel sealed and then heated in a microwave at 6O0C for 30min. The reaction mixture was then concentrated in vacuo, diluted with DCM (50ml) and aqueous ammonia solution (50ml), the organic phase separated, washed with brine (2 x 25ml), dried (MgSO4) and concentrated in vacuo. Chromatography (SiO2, 4:6 EtOAc: hexanes) gave tert-butyl 4-(3-(3,5-dichloro-4-(N- (difluoromethyl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfamoyl)phenyl)propyl)piperidine-1- carboxylate as a colourless gum. The above named compound in DCM (10ml) was treated with trifluoroacetic acid (1ml), stirred at rt for 1h then concentrated in vacuo. The residual gum was diluted with DCM (25ml) and aqueous ammonia (25ml), the organic phase separated, dried (MgSO4) and concentrated. Dilution with DCM (10ml), treatment with HCI (1M in diethyl ether, 2ml) followed by filtration under a stream of argon gave the title compound as a white hygroscopic powder (210mg, 0.385mmol, 60%). δH (D2O, 300K) 7.29 (1 H, t J 60.0Hz), 7.22 (2H, s), 3.40 (3H, s), 3.13 (2H, d J 13.2Hz), 2.68 (2H, t J 11.7Hz), 2.36 (2H, s br), 1.66 (3H, s), 1.61-0.95 (9H, complex), 1.46 (3H, s). m/z (ES+, 70V) 509.2 (MH+).
EXAMPLE DDD100097 2,6-dichloro-N-(difluoromethyl)-4-(3-(1-methyIpiperidin-4-yI)propyl)-N-(1,3,5- trimethyl-1H-pyrazol-4-yl)benzenesulfonamide
Prepared from 4-allyl-1-methylpiperidine (776mg, 5.54mmol) and the compound of intermediate 40 (2.5g, 5.4mmol) according to the method of compound DDD100096 to give the title compound as a white powder (2.41 g, 4.6mmol, 85%), δH (D-6 DMSO 300K) 7.36 (1H, t J 59.6Hz), 7.58 (2H, s), 3.64 (3H, s), 3.35 (2H, dm), 3.2-3.0 (1H, m br), 2.86 (2H, m), 2.69 (2H, m), 2.66 (2H, t J 7.5Hz), 1.88 (3H, s), 1.83 (3H, m), 1.66 (3H, s), 1.65- 1.57 (2H, m), 1.50-1.39 (2H, m), 1.24-1.17 (2H, m). m/z (ES+, 70V) 523.2 (MH+).
EXAMPLE DDD100144 2,6-dichloro-N-(dif luoromethyl)-4-(4-(1 -methylpiperidin-4-yl)butyl)-N-(1 ,3,5- trimethyl-1H-pyrazol-4-yl)benzenesulfonamide
Prepared from 4-(but-3-enyl)-1-methylpiperidine (320mg, 2.14mmol) and the compound of intermediate 40 (500mg, 1.08mmol) according to the method of compound DDD100096 to give the title compound as a white powder (197mg, 34%), δH (D-6 DMSO 500K) 10.06 (1 H, bs); 7.69 (1 H, t, J 60Hz); 7.61 (2H, s); 3.64 (3H1 s); 3.36 (2H, m); 2.80 (5H, m); 2.65 (2H, m); 1.88 (3H, s); 1.79 (2H, m); 1.59 (3H, s); 1.57 (2H, m); 1.32 (7H, m). m/z (ES+, 70V) 537.2 (MH+).
EXAMPLE DDD100153 ajθ-dichloro^-tS^I-methylpiperidin^-yOpropylJ-N^a^^-trifluoroethylJ-N-li.S.δ- trimethyl-1H-pyrazol-4-yl)benzenesulfonamide
Prepared from 4-allyl-1-methylpiperidine (448mg, 3.2mmol) and the compound of intermediate 47 (790mg, 1.6mmol) according to the method of DDD100096 to give the title compound as a colourless oil (784mg, 1.41 mmol, 88%). δH (CDCI3, 300K) 7.20 (2H, s), 4.87-4.73 (1H1 m), 3.94-3.67 (1H1 m), 3.67 (3H, s), 3.29 (2H, brd, J = 7.3 Hz), 2.63- 2.52 (5H, m), 2.40 (2H, brs), 2.18 (3H, s), 1.79 (4H, brd, J = 13.5 Hz), 1.61 (3H, s), 1.56 (1H, brs), 1.34-1.29 (4H, m). m/z (ES+, 70V) 555.1 (MH+).
EXAMPLE DDD100798 N-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)-4-(2,3,4,5-tetrahydro-1H-benzo[c]azepin- 8-yl)benzenesulfonamide Hydrochloride
Prepared from the boronic ester of intermediate 42 (321 mg, 0.71 mmol), 8-Bromo- 2,3,4,5-tetrahydro-1H-2-benzazepine (160mg, 0.71 mmol, prepared according to the methods cited by H. Stark et al, ChemBioChem, 2004, 5, 508-518 and G.LGrunewald et al, Bioorg. Med. Chem., 9, 2001, 1957-1965), tribasic potassium phosphate (150mg, 0.71 mmol), and Pd(PPh3)4 (30mg, 0.026mmol) in DMF (5ml) and water (1.5ml), according to the method of intermediate 11 , Dilution with DCM (10ml), treatment with HCI (1M in diethyl ether, 2ml) followed by evaporation, trituration with ether and filtration under a stream of argon gave the title compound as a white hygroscopic powder (300mg, 0.61 mmol, 87%). δH (D-6 DMSO, 500K) 9.15 (1H, s), 9.04 (1H, bs), 7.87 (2H, d J 8.6Hz), 7.85 (1H, d J 1.9 Hz), 7.72 (2H, d J 8.6Hz), 7.68 (1 H, dd J 7.9Hz 1.9Hz), 7.41 (1 H, d J 7.9Hz), 4.41 (2H, m), 3.56 (3H, s), 3.37 (2H, m), 3.04 (2H, m), 1.90 (4H, m), 1.77 (3H, s), 1.72 (1H, m), 1.70 (6H, d J 6.6Hz). m/z (ES+, 70V) 453.3 (MH+).
EXAMPLE 100868
N-{3-isobutyl-1 ,5-dimethyl-1 H-pyrazol-4-yl)-4-(2-methyl-2,3,4,5-tetrahydro-1 H- benzo[c]azepin-8-yl)benzenesulfonamide Hydrochloride
The amine of Example DDD100798 (150mg, 0.31 mmol) was taken up in formic acid (10ml) and paraformaldehyde (92mg, 3.10mmol) added. The reaction mixture was heated at 850C for 18h then allowed to cool and concentrated to dryness. The residue was basified with aqueous ammonia solution (20ml), extracted with DCM (20ml) and the organics concentrated in vacuo to give a gum which was subjected to chromatography (SiO2, 94:5:1 DCM: MeOH: saturated aqueous ammonia solution). Dilution with DCM (10ml), treatment with HCI (1 M in diethyl ether, 2ml) followed by evaporation, trituration with ether and filtration under a stream of argon gave the title compound as a white hygroscopic powder (60mg, 0.12mmol, 39%). δH (D2O, 500K) 7.81 (2H, m), 7.77 (2H, m), 7.68 (2H1 m), 7.42 (1 H, m), 4.56 (1 H, m), 3.71 (1 H, m), 3.69 (3H, s), 3.51 (1 H, m), 3.08 (2H1 m), 2.88 (3H1 bs), 2.15 (1 H, m), 1.98 (3H, s), 1.95 (1 H1 m), 1.89 (2H1 m), 1.64 (1H, m), 0.67 (6H, d J 6.7Hz). m/z (ES+, 70V) 467.3 (MH+).
Biological Data
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Table 1. Enzyme and Cellular Activity of N-Myristoyltransferase Inhibitors
Enzyme activities are for T. brucei NMT. Where present, Human (/-/ι/NMT-1), Aspergillus fumigatus (>A/NMT) and Leishmania major (LmNMT) enzyme inhibition data are given in parentheses. Cellular activitites are for inhibition of T. brucei brucei (blood stream form, variant 221).
Figure imgf000161_0002
Table 2. Activity of N-Myristoyltransferase Inhibitors Against Human Cancer
Cell Lines
Figure imgf000161_0003
Table 3. Activity of N-Myristoyltransferase Inhibitors Against Human Cancer
Cell Lines
Figure imgf000162_0001
Table 4. Activity of N-Myristoyltransferase Inhibitors Against Human Cancer
Cell Lines
Assessment of the CNS penetration of NMT inhibitors was determined in the female NMRI mouse following i.v. dosing (n=3 per dose group, concentration measured after t = 5min).
Figure imgf000162_0002
Table 5. Drug concentration in blood and brain in the female NWlRI mouse at t = 5min following single Lv. dosing (average of three animals)
Assessment of the antitrypanosomal efficacy of DDD85646 in an acute model of trypanosomiasis was determined at six dose levels in the female NMRI mouse (n=3 per dose group). Compound was dosed for four days b.i.d. at the stated level, commencing three days after infection with 1 x 104 trypanosomes (T brucei brucei, blood stream form, variant 221).

Claims

1. A compound of formula (I)
Figure imgf000164_0001
(I) or formula (II)
Figure imgf000164_0002
(II) wherein
n is 0,1, 2, 3, 4, 5 or 6;
ring A, herein referred to as a "head" group, is an optionally substituted nitrogen containing aryl group wherein each substitutable carbon or nitrogen in Ring A is optionally and independently substituted by one or more R5 and wherein if Ring A contains an -NH- moiety that nitrogen may be optionally substituted by C-ι-6 alkyl (e.g. methyl); and wherein R4 and ring A together with the atoms to which they are attached may form a cyclic group.
ring B is an optionally substituted aryl or heteroaryl group wherein each substitutable carbon or heteroatom in Ring B is optionally and independently substituted by one or more R3;
W and X, one of which may be absent, are independently selected from R11, hydrocarbyl (e.g. Ci-6 alkyl, alkenyl, alkynyl.or haloalkyl) optionally substituted with R11, and -(CH2)k-heterocyclyl optionally substituted with R12; k is 0, 1 , 2, 3, 4, 5 or 6;
R1, R2, R3, R4 and R5 are independently selected from hydrogen, R12, hydrocarbyl (e.g. Ci-6 alkyl, alkenyl, alkynyl.or haloalkyl) optionally substituted with R12, and - (CH2)ι-heterocyclyl optionally substituted with R12; wherein R1 and R2 taken together with the atoms to which they are attached may form a heterocycle, optionally substituted with one or more R12; wherein R1 and/or R2 taken together with W or X may form a heterocycle optionally substituted with one or more R12; and wherein one or more of R3 and R5 taken together with the atoms to which they are attached may form a carbocycle, for example heterocyclyl, optionally substituted with R12; I is 0, 1 , 2, 3, 4, 5 or 6;
wherein each R11 and R12 is independently selected from halogen, trifluoromethyl, cyano, thio, nitro, oxo, =NR13, -OR13, -SR13, -C(O)R13, - C(O)OR13, -OC(O)R13, -NR13COR14, -NR13CONR13 2, -NR13COR14, - NR13CO2R14, -S(O)R13, -S(O)2R13, -SONR13 2, -NR13S(O)2R14; -CSR13, -N(R13)R14, -C(O)N(R13)R14, -SO2N(R13)R14 and R15;
wherein R13 and R14 are each independently selected from hydrogen or R15;
wherein R15 is selected from hydrocarbyl (e.g. Ci-6 alkyl, alkenyl, alkynyl.or haloalkyl), carbocyclyl and -(CH2)m-heterocyclyl, and each R15 is optionally and independently substituted with one or more of halogen, cyano, amino, hydroxy, Ci-6 alkyl and Ci-6 alkoxy; m is 0, 1 , 2, 3, 4, 5 or 6;
p is 0, 1 , 2, 3 or 4; wherein the values of R4 may be the same or different; q is 0, 1 , 2, 3 or 4; wherein the values of R5 may be the same or different;
Y and Z1 one or both of which may be absent, are independently selected from hydrogen, R16, hydrocarbyl (e.g. Ci-6 alkyl, alkenyl, alkynyl.or haloalkyl) optionally substituted with R16, and -(CH2)r-heterocyclyl optionally substituted with R16, wherein each R16 is independently selected from halogen, trifluoromethyl, cyano, thio, nitro, oxo, =NR17, -OR17, -SR17, -C(O)R17, -C(O)OR17, -OC(O)R17, - NR17COR18, -NR17CONR182, -NR17COR18, -NR17CO2R18, -S(O)R17, -S(O)2R17, - SONR17 2, -NR17S(O)2R18; -CSR17, -N(R17)R18, -C(O)N(R17)R18, -SO2N(R17)R18 and R19; r is O, 1 , 2, 3, 4, 5 or 6;
wherein R17 and R18 are each independently selected from hydrogen or R19;
wherein R19 is selected from hydrocarbyl (e.g.Ci_6 alkyl, alkenyl, alkynyl.or haloalkyl), carbocyclyl and -(CH2)s-heterocyclyl, and each R19 is optionally and independently substituted with one or more of halogen, cyano, amino, hydroxy, Ci-6 alkyl and d-6 alkoxy; s is O, 1, 2, 3, 4, 5 or 6;
or a pharmaceutically acceptable salt or pro-drug thereof.
2. A compound as claimed in claim 1 wherein Ring A is 5 or 6 membered nitrogen containing heteroaryl.
3. A compound as claimed in claim 2 wherein ring A is a 5 membered nitrogen-containing heteroaryl selected from the group consisting of pyrazole, imidazole, imidazoline, triazole and tetrazole.
4. A compound as claimed in claim 2 wherein ring A is a 6 membered nitrogen-containing heteroaryl selected from the group consisting of pyridine, 3 amino pyridine, 4 amino pyridine, pyridazine, pyrimidine, pyrazine, triazine and tetrazine.
5. A compound as claimed in claim 2 wherein ring A is selected from pyrazole, pyridine or isoxazole.
6. A compound as claimed in claim 5 wherein ring A is pyrazole.
7. A compound as claimed in any preceding claim wherein the compound is of formula (III)
Figure imgf000167_0001
(III)
8. A compound as claimed in claim 7 wherein the compound is of formula
(HI)(O
Figure imgf000168_0001
(Nl)O)
wherein R5a, R5b and R5c are independently selected from hydrogen, R12, hydrocarbyl (e.g. C1-6 alkyl, alkenyl, alkynyl.or haloalkyl) optionally substituted with R12, and -(CH2)ι-heterocyclyl optionally substituted with R12.
9. A compound as claimed in wherein claim 8 wherein R5a is Ci.6 alkyl.
10. A compound as claimed in wherein claim 9 wherein R5a is methyl.
11. A compound as claimed in any preceding claim wherein Ring B is a 5 or 6 membered aryl or heteroaryl.
12. A compound as claimed in claim 11 wherein ring B is a 6 membered aryl.
13. A compound as claimed in claim 11 wherein Ring B is a 5 membered heteroaryl containing one or more heteroatoms selected from N, S and O.
14. A compound as claimed in claim 11 wherein ring B is a 6 membered heteroaryl containing one or more heteratoms selected from N, S and O.
15. A compound as claimed in claim 14 wherein ring B is a nitrogen containing heteroaryl.
16. A compound as claimed in claim 15 wherein ring B is pyridine.
17. A compound as claimed in any one of claims 1 to 12 or 14 to 16 wherein the compound is of formula IV
Figure imgf000169_0001
(IV)
wherein E is independently selected from C and N.
18. A compound as claimed in claim 17 wherein E is N.
19. A compound as claimed in claim 17 wherein E is C.
20. A compound as claimed in any one of claims 17 to 20 wherein the compound is of formula (IV)(i)
Figure imgf000170_0001
(IV)(O
21. A compound as claimed in claim 20 wherein the compound is of formula (IV)(U)
Figure imgf000170_0002
(IV)(U) wherein R3a, R3b, R3c and R3d are independently selected from hydrogen, R12, hydrocarbyl (e.g.C-ι-6 alkyl, alkenyl, alkynyl.or haloalkyl) optionally substituted with R12, and -(CH2)ι-heterocyclyl optionally substituted with R12.
22. A compound as claimed in claim 21 wherein R3a, R3b, R3c and R3d are independently selected from hydrogen, halogen and C-i-6 alkyl or haloalkyl.
23. A compound as claimed in claim 22 wherein R3a, R3b, R3c and R3d are independently selected from hydrogen and halogen.
24. A compound as claimed in any one of claims 21 to 23 wherein the compound is of formula (IV)(Ui)
Figure imgf000171_0001
(IV)(Ui)
wherein R5a, R5b and R5c are as defined in claim 8.
25. A compound as claimed in claim 24 wherein R3a and/or R3b is halogen.
26. A compound as claimed in claim 25 wherein R3a and/or R3b Cl or F.
27. A compound as claimed in any one preceding claim wherein W is absent and X is carbocyclyl optionally substituted with one or more R12.
28. A compound as claimed in claim 27 wherein X is aryl or heterocyclyl optionally substituted with one or more R12.
29. A compound as claimed in claim 28 wherein X is heteroaryl optionally substituted with one or more R12.
30. A compound as claimed in any one preceding claim wherein R1 and R2 are joined with the N of -NR1R2 to form a saturated five to seven membered protonatable N-containing heterocycle optionally substituted with one or more R12.
31. A compound as claimed in any one of claims 1 to 30 wherein at least one of R1 or R2 is an amine.
32. A compound as claimed in any one preceding claim wherein R4 is selected from hydrogen and Ci-β alkyl optionally substituted with halogen, cyano, amino, t hydroxy, C1-6 alkyl and Ci-6 alkoxy or carbocyclyl.
33. A compound as claimed in claim 32 wherein R4 is C1-6 alkyl optionally substituted with fluoro.
34. A compound as claimed in any one of claims 1 to 10 or 27 to 33 wherein the compound is of formula V
Figure imgf000173_0001
(V)
wherein t is 0, 1 , 2, 3, 4, 5 or 6; ring D is an optionally substituted nitrogen containing 6 or 7 membered heterocycle, for example piperidine, wherein each substitutable carbon or nitrogen in Ring D is optionally and independently substituted by one or more R7; R7 is independently selected from hydrogen, R20, hydrocarbyl (e.g. Ci-6 alkyl, alkenyl, alkynyl.or haloalkyl) optionally substituted with R20, and -(CH2)V- heterocyclyl optionally substituted with R20; v is 0, 1 , 2, 3, 4, 5 or 6;
wherein each R20 is independently selected from halogen, trifluoromethyl, cyano, thio, nitro, oxo, =NR21, -OR21, -SR21, -C(O)R21, -C(O)OR21, - OC(O)R21, -NR21COR22, -NR21CONR22,, -NR21COR22, -NR21CO2R22, -S(O)R21, -S(O)2R21, -SONR21 2, -NR21S(O)2R22; -CSR21, -N(R21)R22, -C(O)N(R21)R22, -SO2N(R21)R22 and R23;
wherein R21 and R22 are each independently selected from hydrogen or R23;
wherein R23 is selected from hydrocarbyl (e.g.Ci-6 alkyl, alkenyl, alkynyl.or haloalkyl), carbocyclyl and -(CH2)w-heterocyclyl, and each R23 is optionally and independently substituted with one or more of halogen, cyano, amino, hydroxy, C1-6 alkyl and C1-6 alkoxy; w is O, 1, 2, 3, 4, 5 or 6;
R8 is selected from the list of optional substituents represented by the group R4.
35. A compound as claimed in claim 34 wherein the compound is of formula (V)(i)
Figure imgf000174_0001
(V)O)
36. A compound as claimed in claim 34 or claim 35 wherein R8 is hydrogen or methyl.
37. A compound as claimed in any one of claims 1 to 10 or 27 to 33 wherein the compound is of formula Vl
Figure imgf000175_0001
R8
(Vl)
wherein ring D is an optionally substituted nitrogen containing 6 or 7 membered heterocycle wherein each substitutable carbon or nitrogen in Ring D is optionally and independently substituted by one or more R7.
38. A compound as claimed in claim 37 wherein ring B is phenyl or pyridinyl.
39. A compound as claimed in claim 37 wherein W is Chalky!.
40. A compound as claimed in claim 37 W is cycloalkyl.
41. A compound as claimed in any one of claims 37 to 40 wherein the compound is of formula (Vl)(i)
Figure imgf000176_0001
42. A compound as claimed in any one of claims 1 to 10, 27 to 33 or 37 to 40 wherein the compound is of formula VII
Figure imgf000176_0002
(VIl) wherein u is 0, 1 , 2, 3, 4, 5 or 6; ring C is an optionally substituted cyclic group wherein each substitutable carbon or heteroatom in Ring C is optionally and independently substituted by one or more R6;
R6 is independently selected from hydrogen, R20, hydrocarbyl (e.g.Ci-6 alkyl, alkenyl, alkynyl, or haloalkyl) optionally substituted with R20, and -(CH2)V- heterocyclyl optionally substituted with R20; v is 0, 1 , 2, 3, 4, 5 or 6;
wherein each R20 is independently selected from halogen, trifluoromethyl, cyano, thio, nitro, oxo, =NR21, -OR21, -SR21, -C(O)R21, -C(O)OR21, - OC(O)R21, -S(O)R21, -S(O)2R21, -N(R21)R22, -C(O)N(R21)R22, - SO2N(R21)R22 and R23;
wherein R21 and R22 are each independently selected from hydrogen or
R23;
wherein R23 is selected from hydrocarbyl (e.g.Ci-6 alkyl, alkenyl, alkynyl, or haloalkyl), carbocyclyl and -(CH2)w-heterocyclyl, and each R23 is optionally and independently substituted with one or more of halogen, cyano, amino, hydroxy, Ci-6 alkyl and Ci-6 alkoxy; w is 0, 1 , 2, 3, 4, 5 or 6.
43. A compound as claimed in claim 42 wherein Ring C is aryl.
44. A compound as claimed in claim 42 wherein Ring C is heterocyclyl.
45. A compound as claimed in any one of claims 42 to 44 wherein the compound is of formula Vll(i)
Figure imgf000178_0001
R0
(VII)(O
46. A compound as claimed in any one of claims 42 to 45 wherein the compound is of formula VIII
Figure imgf000178_0002
(VIII) wherein G is independently selected from C and N.
47. A compound of formula IX
Figure imgf000179_0001
(IX)
wherein n, n', E, X, R3, R4, R5, p and q are as defined herein and wherein J is independently a nitrogen containing heterocycle or an amine.
48. A compound, or pharmaceutically acceptable salt thereof, as claimed in any one of the preceding claims for use as a medicament.
49. Use of a compound, or pharmaceutically acceptable salt thereof, as claimed in any one of the preceding claims in the manufacture of a medicament for the treatment or prevention of a N-myristoyl transferase (NMT) related disease or disorder.
50. Use as claimed in claim 49 wherein the NMT related disease or disorder includes hyperproliferative disorders, microbial infections, neurological diseases/disorders and diabetes.
51. Use as claimed in claim 50 wherein the hyperproliferative disorder is cancer.
52. Use as claimed in claim 50 wherein the microbial infection is a parasite, viral or fungal infection.
53. A method of treating a NMT related disease or disorder in a subject which method comprises administering to said subject a therapeutically effective amount of a compound as claimed in any one of claims 1 to 47, or pharmaceutically acceptable salt thereof.
54. A method of inhibiting the activity of one or more NMT, said method comprising contacting one or more NMT with an effective amount of a compound as claimed in any one of claims 1 to 47.
55. A package or kit of parts comprising: (1) a compound as claimed in any one of claims 1 to 47, or pharmaceutically acceptable salt thereof; together with
(2) instructions to use said compound or salt in a method as claimed in claim 53 or 54.
56. A N-heterocyclic sulphonamide compound for use as a medicament.
57. A compound as claimed in claim 56 which is a N-heteroaryl sulphonamide.
58. A compound as claimed in claim 57 which is a pyrazole sulphonamide.
59. A compound as claimed in claim 58 which is of formula (I) as defined herein in claim 1.
60. A compound as claimed in claim 48 which is of formula (II) as defined in claim 1.
PCT/GB2009/002084 2008-09-02 2009-08-29 N-myristoyl transferase inhibitors WO2010026365A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US13/061,811 US9156811B2 (en) 2008-09-02 2009-08-29 N-myristoyl transferase inhibitors
EP09785018.4A EP2323987B1 (en) 2008-09-02 2009-08-29 N-myristoyl transferase inhibitors
ES09785018.4T ES2546865T3 (en) 2008-09-02 2009-08-29 N-myristoyl transferase inhibitors
US14/840,660 US9828346B2 (en) 2008-09-02 2015-08-31 N-myristoyl transferase inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0815947.7A GB0815947D0 (en) 2008-09-02 2008-09-02 Compounds
GB0815947.7 2008-09-02

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US13/061,811 A-371-Of-International US9156811B2 (en) 2008-09-02 2009-08-29 N-myristoyl transferase inhibitors
US14/840,660 Continuation US9828346B2 (en) 2008-09-02 2015-08-31 N-myristoyl transferase inhibitors

Publications (1)

Publication Number Publication Date
WO2010026365A1 true WO2010026365A1 (en) 2010-03-11

Family

ID=39866103

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2009/002084 WO2010026365A1 (en) 2008-09-02 2009-08-29 N-myristoyl transferase inhibitors

Country Status (5)

Country Link
US (2) US9156811B2 (en)
EP (2) EP2323987B1 (en)
ES (2) ES2631227T3 (en)
GB (1) GB0815947D0 (en)
WO (1) WO2010026365A1 (en)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7994185B2 (en) 2008-05-06 2011-08-09 Glaxo Smith Kline LLC Benzene sulfonamide thiazole and oxazole compounds
WO2011121309A1 (en) 2010-03-31 2011-10-06 Takeda Pharmaceutical Company Limited Phenyl sulfonyl derivatives and their use as histamine h3 antagonists
WO2013083991A1 (en) 2011-12-06 2013-06-13 Imperial Innovations Limited Novel compounds and their use in therapy
JP2013525438A (en) * 2010-04-29 2013-06-20 アメリカ合衆国 Human pyruvate kinase activator
WO2013122897A1 (en) * 2012-02-13 2013-08-22 Amgen Inc. Dihydrobenzoxazine and tetrahydroquinoxaline sodium channel inhibitors
EP2734199A1 (en) * 2011-07-22 2014-05-28 Pacylex Pharmaceuticals Inc. Synthetic lethality and the treatment of cancer
US9051311B2 (en) 2012-03-09 2015-06-09 Amgen Inc. Sulfamide sodium channel inhibitors
CN104768550A (en) * 2012-10-30 2015-07-08 厄尔莱克斯制药公司 Synthetic lethality and the treatment of cancer
US10448637B2 (en) * 2014-10-03 2019-10-22 Arizona Board Of Regents On Behalf Of The University Of Arizona Inhibitors of GRB2-associated binding protein 1 (GAB1) and methods of treating cancer using the same
WO2020128475A1 (en) 2018-12-19 2020-06-25 Imperial College Innovations Limited Cancer treatments
WO2020128473A1 (en) 2018-12-19 2020-06-25 Imperial College Innovations Limited Novel compounds and their use in therapy
WO2021008512A1 (en) * 2019-07-18 2021-01-21 石药集团中奇制药技术（石家庄）有限公司 Compound as nmt inhibitor and use thereof
CN112638898A (en) * 2018-08-31 2021-04-09 泽农医药公司 Heteroaryl substituted sulfonamide compounds and their use as sodium channel inhibitors
WO2022058745A2 (en) 2020-09-18 2022-03-24 Imperial College Innovations Limited Novel compounds and their use in therapy
WO2022090746A1 (en) 2020-11-02 2022-05-05 Imperial College Innovations Limited Nmt inhibitors for treating senescence-associated diseases or disorders
US11788145B2 (en) 2015-07-17 2023-10-17 Pacylex Pharmaceuticals Inc. Epigeneiic silencing of NMT2
WO2024052685A1 (en) 2022-09-09 2024-03-14 MyricX Pharma Limited Cytotoxic imidazo[1,2-a]pyridine compounds and their use in therapy
JP7450606B2 (en) 2018-08-31 2024-03-15 ゼノン・ファーマシューティカルズ・インコーポレイテッド Heteroaryl-substituted sulfonamide compounds and their use as therapeutic agents

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB201511382D0 (en) 2015-06-29 2015-08-12 Imp Innovations Ltd Novel compounds and their use in therapy
CA3090385A1 (en) 2018-02-05 2019-08-08 Alkermes, Inc. Compounds for the treatment of pain
CA3121202A1 (en) 2018-11-30 2020-06-04 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
CN113318107B (en) * 2021-07-08 2022-07-12 中国科学院微生物研究所 Application of nitrogen-containing compound in preparation of antifungal medicine

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5266576A (en) * 1991-02-11 1993-11-30 Adir Et Compagnie N-myristoyl transferase inhibitors
WO2000037464A2 (en) * 1998-12-18 2000-06-29 Basilea Pharmaceutica Ag 4-(aminoalkoxy)benzofurans as n-myristoyltransferase inhibitors
WO2001044239A2 (en) * 1999-12-15 2001-06-21 Bristol-Myers Squibb Co. Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists
WO2004074288A1 (en) * 2003-02-19 2004-09-02 F. Hoffmann-La Roche Ag Sulfonamide substituted xanthine derivatives for use as pepck inhibitors
JP2006070014A (en) * 2004-08-04 2006-03-16 Hisamitsu Medical Kk 2-aminobenzothiazole derivative
WO2007076055A2 (en) * 2005-12-22 2007-07-05 Entremed, Inc. Compositions and methods comprising proteinase activated receptor antagonists
WO2008118758A1 (en) * 2007-03-23 2008-10-02 Icagen, Inc. Inhibitors of ion channels
US20090163545A1 (en) * 2007-12-21 2009-06-25 University Of Rochester Method For Altering The Lifespan Of Eukaryotic Organisms

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE539752T1 (en) * 2006-08-16 2012-01-15 Exelixis Inc USE OF PI3K AND MEK MODULATORS IN CANCER TREATMENT
WO2009013348A2 (en) * 2007-07-26 2009-01-29 Novartis Ag Pyrimidine derivatives useful for the treatment of inflammatory or allergic conditions

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5266576A (en) * 1991-02-11 1993-11-30 Adir Et Compagnie N-myristoyl transferase inhibitors
WO2000037464A2 (en) * 1998-12-18 2000-06-29 Basilea Pharmaceutica Ag 4-(aminoalkoxy)benzofurans as n-myristoyltransferase inhibitors
WO2001044239A2 (en) * 1999-12-15 2001-06-21 Bristol-Myers Squibb Co. Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists
WO2004074288A1 (en) * 2003-02-19 2004-09-02 F. Hoffmann-La Roche Ag Sulfonamide substituted xanthine derivatives for use as pepck inhibitors
JP2006070014A (en) * 2004-08-04 2006-03-16 Hisamitsu Medical Kk 2-aminobenzothiazole derivative
WO2007076055A2 (en) * 2005-12-22 2007-07-05 Entremed, Inc. Compositions and methods comprising proteinase activated receptor antagonists
WO2008118758A1 (en) * 2007-03-23 2008-10-02 Icagen, Inc. Inhibitors of ion channels
US20090163545A1 (en) * 2007-12-21 2009-06-25 University Of Rochester Method For Altering The Lifespan Of Eukaryotic Organisms

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 2009, GOLDFARB, DAVID SCOTT: "Method using lifespan-altering compounds for altering the lifespan of eukaryotic organisms, and screening for such compounds", XP002567650, retrieved from STN Database accession no. 2009:846111 *
DEICHAITE ET AL., MOL CELL BIOL, vol. 8, 1988, pages 4295 - 301
KING ET AL., J BIOL CHEM, vol. 264, 1989, pages 7772 - 5
LINDLEY, PETER F. ET AL: "The crystal and molecular structure of N-(1,2,3,5-tetramethyl-4-pyrazolio)toluene-p-sulfonamidate, C14H19N3O2S, a mesoionic pyrazole", ACTA CRYSTALLOGRAPHICA, SECTION B: STRUCTURAL CRYSTALLOGRAPHY AND CRYSTAL CHEMISTRY , B33(7), 2160 CODEN: ACBCAR; ISSN: 0567-7408, 1977, XP002567651 *
PILLAI ET AL., PROC NATL ACAD SCI USA, vol. 84, 1987, pages 7654 - 8
T W GREENE; P G M WUTZ: "Groups in Organic Synthesis", 1991, WILEY-INTERSCIENCE
TOWLER ET AL., J BIOL CHEM, vol. 262, 1987, pages 1030 - 6
WILCOX ET AL., SCIENCE, vol. 238, 1987, pages 1275 - 8
WOLVEN ET AL., MOL BIOL CELL, vol. 8, 1997, pages 1159 - 73

Cited By (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8642759B2 (en) 2008-05-06 2014-02-04 Glaxosmithkline Llc Benzene sulfonamide thiazole and oxazole compounds
US8415345B2 (en) 2008-05-06 2013-04-09 Glaxo SmithKline LLC Benzene sulfonamide thiazole and oxazole compounds
US7994185B2 (en) 2008-05-06 2011-08-09 Glaxo Smith Kline LLC Benzene sulfonamide thiazole and oxazole compounds
US9233956B2 (en) 2008-05-06 2016-01-12 Novartis Ag Benzene sulfonamide thiazole and oxazole compounds
WO2011121309A1 (en) 2010-03-31 2011-10-06 Takeda Pharmaceutical Company Limited Phenyl sulfonyl derivatives and their use as histamine h3 antagonists
US9708267B2 (en) 2010-04-29 2017-07-18 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Activators of human pyruvate kinase
JP2013525438A (en) * 2010-04-29 2013-06-20 アメリカ合衆国 Human pyruvate kinase activator
US20140227284A1 (en) * 2011-07-22 2014-08-14 Pacylex Pharmaceuticals Inc. Synthetic lethality and the treatment of cancer
CN103826623A (en) * 2011-07-22 2014-05-28 厄尔莱克斯制药公司 Synthetic lethality and the treatment of cancer
JP2014523440A (en) * 2011-07-22 2014-09-11 パシレックス・ファーマシューティカルズ・インコーポレイテッド Synthetic lethality and cancer treatment
EP2734199A4 (en) * 2011-07-22 2015-04-01 Pacylex Pharmaceuticals Inc Synthetic lethality and the treatment of cancer
US11135218B2 (en) 2011-07-22 2021-10-05 Pacylex Pharmaceuticals Inc. Synthetic lethality and the treatment of cancer
KR102164964B1 (en) 2011-07-22 2020-10-14 페이실렉스 파마슈티컬스 인코포레이티드 Synthetic lethality and the treatment of cancer
EP2734199A1 (en) * 2011-07-22 2014-05-28 Pacylex Pharmaceuticals Inc. Synthetic lethality and the treatment of cancer
KR20200093065A (en) * 2011-07-22 2020-08-04 페이실렉스 파마슈티컬스 인코포레이티드 Synthetic lethality and the treatment of cancer
CN110115768A (en) * 2011-07-22 2019-08-13 厄尔莱克斯制药公司 The treatment of synthetic lethal and cancer
WO2013083991A1 (en) 2011-12-06 2013-06-13 Imperial Innovations Limited Novel compounds and their use in therapy
WO2013122897A1 (en) * 2012-02-13 2013-08-22 Amgen Inc. Dihydrobenzoxazine and tetrahydroquinoxaline sodium channel inhibitors
US9346798B2 (en) 2012-02-13 2016-05-24 Amgen Inc. Dihydrobenzoxazine and tetrahydroquinoxaline sodium channel inhibitors
US9051311B2 (en) 2012-03-09 2015-06-09 Amgen Inc. Sulfamide sodium channel inhibitors
JP2016506362A (en) * 2012-10-30 2016-03-03 パシレックス・ファーマシューティカルズ・インコーポレイテッド Synthetic lethality and cancer treatment
CN110974967A (en) * 2012-10-30 2020-04-10 厄尔莱克斯制药公司 Synthetic lethality and treatment of cancer
CN110974967B (en) * 2012-10-30 2023-11-07 厄尔莱克斯制药公司 Synthetic mortality and cancer treatment
KR102496892B1 (en) * 2012-10-30 2023-02-06 페이실렉스 파마슈티컬스 인코포레이티드 Synthetic lethality and the treatment of cancer
EP3858350A1 (en) * 2012-10-30 2021-08-04 Pacylex Pharmaceuticals Inc. Synthetic lethality and the treatment of cancer
KR20150079949A (en) * 2012-10-30 2015-07-08 페이실렉스 파마슈티컬스 인코포레이티드 Synthetic lethality and the treatment of cancer
CN104768550A (en) * 2012-10-30 2015-07-08 厄尔莱克斯制药公司 Synthetic lethality and the treatment of cancer
US10448637B2 (en) * 2014-10-03 2019-10-22 Arizona Board Of Regents On Behalf Of The University Of Arizona Inhibitors of GRB2-associated binding protein 1 (GAB1) and methods of treating cancer using the same
US11432547B2 (en) 2014-10-03 2022-09-06 Arizona Board Of Regents On Behalf Of The University Of Arizona Inhibitors of GRB2-associated binding protein 1 (GAB1) and methods of treating cancer using the same
US11788145B2 (en) 2015-07-17 2023-10-17 Pacylex Pharmaceuticals Inc. Epigeneiic silencing of NMT2
CN112638898B (en) * 2018-08-31 2024-04-09 泽农医药公司 Heteroaryl substituted sulfonamide compounds and their use as sodium channel inhibitors
JP2021535137A (en) * 2018-08-31 2021-12-16 ゼノン・ファーマシューティカルズ・インコーポレイテッドXenon Pharmaceuticals Inc. Heteroaryl substituted sulfonamide compounds, and their use as sodium channel inhibitors
JP7450606B2 (en) 2018-08-31 2024-03-15 ゼノン・ファーマシューティカルズ・インコーポレイテッド Heteroaryl-substituted sulfonamide compounds and their use as therapeutic agents
JP7383012B2 (en) 2018-08-31 2023-11-17 ゼノン・ファーマシューティカルズ・インコーポレイテッド Heteroaryl-substituted sulfonamide compounds and their use as sodium channel inhibitors
CN112638898A (en) * 2018-08-31 2021-04-09 泽农医药公司 Heteroaryl substituted sulfonamide compounds and their use as sodium channel inhibitors
WO2020128473A1 (en) 2018-12-19 2020-06-25 Imperial College Innovations Limited Novel compounds and their use in therapy
WO2020128475A1 (en) 2018-12-19 2020-06-25 Imperial College Innovations Limited Cancer treatments
WO2021008512A1 (en) * 2019-07-18 2021-01-21 石药集团中奇制药技术（石家庄）有限公司 Compound as nmt inhibitor and use thereof
WO2022058745A2 (en) 2020-09-18 2022-03-24 Imperial College Innovations Limited Novel compounds and their use in therapy
WO2022090746A1 (en) 2020-11-02 2022-05-05 Imperial College Innovations Limited Nmt inhibitors for treating senescence-associated diseases or disorders
WO2024052685A1 (en) 2022-09-09 2024-03-14 MyricX Pharma Limited Cytotoxic imidazo[1,2-a]pyridine compounds and their use in therapy
WO2024052684A1 (en) 2022-09-09 2024-03-14 MyricX Pharma Limited Antibody drug conjugate comprising nmt inhibitor and its use

Also Published As

Publication number Publication date
EP2980076B1 (en) 2017-05-31
EP2323987B1 (en) 2015-06-24
US9156811B2 (en) 2015-10-13
ES2631227T3 (en) 2017-08-29
US20110312921A1 (en) 2011-12-22
GB0815947D0 (en) 2008-10-08
ES2546865T3 (en) 2015-09-29
EP2980076A1 (en) 2016-02-03
US20160060224A1 (en) 2016-03-03
EP2323987A1 (en) 2011-05-25
US9828346B2 (en) 2017-11-28

Similar Documents

Publication Publication Date Title
EP2980076B1 (en) Pyrazolyl derivatives
EP0844877B1 (en) Use of oxido-squalene cyclase inhibitors to lower blood cholesterol
KR100736012B1 (en) Benzazole derivatives and their use as ??? modulators
TWI261055B (en) Rho-Kinase Inhibitors
US5942517A (en) 5-(heterocyclic alkyl)-6-aryl-dihydropyrimidines
EP0925286B1 (en) Substituted pyrimidine derivatives and their pharmaceutical use
TW201326138A (en) Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
CN101918395B (en) Triazole oxadiazoles derivatives
JP2003528095A (en) GSK3. 2-amino-3- (alkyl) -pyrimidone derivatives as beta inhibitors
AU2009232721B2 (en) Pyrimidine derivative having cell protecting effect and uses thereof
KR20030031483A (en) Substituted pyrrolopyridinone derivatives useful as phosphodiesterase inhibitors
CN111440189A (en) Fused ring pyrimidine amino derivative, preparation method, intermediate, pharmaceutical composition and application thereof
CA2806634A1 (en) Substituted cyclic carboxamide and urea derivatives as ligands of the vanilloid receptor
MX2007006598A (en) Triazole compounds suitable for treating disorders that respond to modulaiont of the dopamine d3 receptor.
IL160874A (en) 4-imidazolin-2-one derivatives and pharmaceutical compositions containing the same
WO2001070725A1 (en) 2-[indanylamino]pyrimidone and 2-[tetrahydronaphthalenylamino]pyrimidone derivatives
CN101479277A (en) Pyrimidine derivatives as PI3K inhibitors
AU769186C (en) Imidazolones and their use in treating benign prostatic hyperplasia and other disorders
JPH107658A (en) Derivative of sulfonyl ureidopyrazole

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09785018

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2009785018

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 13061811

Country of ref document: US